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Susan E Bates - One of the best experts on this subject based on the ideXlab platform.
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responses to Romidepsin in patients with cutaneous t cell lymphoma and prior treatment with systemic chemotherapy
Leukemia & Lymphoma, 2018Co-Authors: Madeleine Duvic, Richard Piekarz, Susan E Bates, Youn H Kim, Adam Lerner, Tadeusz Robak, Jurgen C Becker, Alexey Samtsov, Robin Eisch, William MccullochAbstract:Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas that typically present in the skin but can progress to systemic involvement. The optimal treatment for patients who relapse from or are refractory to systemic chemotherapy remains unclear. Romidepsin is a potent, class-I selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had ≥1 prior systemic therapy. Here, we present a subanalysis of two phase-2 trials (NCT00106431, NCT00007345) of Romidepsin in patients with CTCL who had prior treatment with systemic chemotherapy. Patients with prior chemotherapy were able to achieve durable responses to Romidepsin, and response rates were similar to those in patients who were chemotherapy naive. Overall, no new safety signals emerged in patients who had received prior chemotherapy. The data presented here suggest that Romidepsin is safe and effective in patients with CTCL who received prior systemic chemotherapy.
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Romidepsin in peripheral and cutaneous t cell lymphoma mechanistic implications from clinical and correlative data
British Journal of Haematology, 2015Co-Authors: Susan E Bates, Miles H Prince, Robin Eisch, Steven L Allen, Mark Kirschbaum, Maria L Turner, Alexander Ling, Douglas R Rosing, Stefania Pittaluga, Jasmine ZainAbstract:Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving Romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to disease regression. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of Romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.
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Romidepsin in peripheral and cutaneous t cell lymphoma mechanistic implications from clinical and correlative data
British Journal of Haematology, 2015Co-Authors: Susan E Bates, Miles H Prince, Robin Eisch, Steven L Allen, Mark Kirschbaum, Maria L Turner, Alexander Ling, Douglas R Rosing, Stefania Pittaluga, Jasmine ZainAbstract:Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving Romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of Romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.
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abstract b9 activated mapk pathway mediates resistance to Romidepsin via bim degradation in Romidepsin selected hut 78 cells
Clinical Cancer Research, 2012Co-Authors: Arup R Chakraborty, Richard Piekarz, Robert W Robey, Victoria Luchenko, Jeanpierre Gillet, Michael M Gottesman, Nathan Collie, Susan E BatesAbstract:Acquired and intrinsic resistance to histone deacetylase inhibitors (HDIs), a new targeted group of anti-tumor agents, limits their clinical efficacy. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. To investigate molecular mechanisms of resistance to the HDI Romidepsin (Dp), we studied a cutaneous T-cell lymphoma (CTCL) cell line, HuT 78, independently selected in verapamil (Vp) or valspodar (PSC833) to prevent the emergence of P-glycoprotein (Pgp), a known resistance mechanism. The HuT 78 sublines DpVp 50 and DpP 75 display 100-200-fold resistance to Romidepsin, not due to Pgp expression. A custom-made Taqman low density gene expression array detected increased expression of insulin receptor (IR) in the resistant cells. Real-time PCR analysis confirmed the results of gene array and detected more than 50-fold upregulation of IR in the Romidepsin-selected cells compared to the parental cells. Increased phosphorylation (5- to 8- fold) of mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. While HuT 78 cells were insensitive to MEK inhibition, resistant cells were found to be exquisitely sensitive to MEK inhibition (IC50
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abstract 4708 short term Romidepsin treatment combined with mitogen activated protein kinase and phosphatidylinositol 3 kinase inhibition causes increased bim expression and cell death in kras mutant cell lines
Cancer Research, 2012Co-Authors: Julian C Bahr, Robert W Robey, Victoria Luchenko, Arup Chakraborty, Susan E BatesAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Romidepsin (FK228) is a histone deacetylase inhibitor (HDI) that modulates chromatin and activates apoptotic pathways in vitro. Clinical efficacy observed in peripheral and cutaneous T-cell lymphoma has not been replicated in solid tumors, as for other HDIs. We thus sought drug combinations that might improve the activity of Romidepsin in solid tumors. Mutations in KRAS induce the mitogen activated protein kinase pathway (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathway. Laboratory data have suggested that activated MEK or AKT can confer resistance to HDIs. To determine if mitogen-activated protein kinase kinase (MEK) or AKT inhibitors could increase sensitivity to Romidepsin, we measured cell death by annexin assay in a panel of 20 cell lines, nine KRAS mutants and eleven KRAS wild-type (WT). Cells were exposed to 25 ng/ml Romidepsin for 6 h in the presence of 250 nM MEK inhibitor PD0325901 and/or 1 µM AKT inhibitor MK2206, after which Romidepsin was removed and cells were incubated with the inhibitors alone for an additional 42 h. Among the 20 solid tumor cell lines examined, those harboring a KRAS mutation had a higher percentage of cell death than lines with WT KRAS when treated with the PD0325901/Romidepsin combination (46.1±18% vs. 21.6±7.6% respectively, p-value .0057), the MK2206/Romidepsin combination (43.8±15.8% vs. 28.6±13.6%, respectively, p-value .0470), or the PD0325901/MK2206/Romidepsin combination (66.5±14.8% vs. 35.0±18.8%, respectively, p-value .0008). There was no statistically significant difference (p-value > .05) in cell death between KRAS and WT cell lines treated with any of the compounds alone. As expression of the pro-apoptotic protein Bim has been associated with Romidepsin-mediated cell death, and as the MAPK pathway has been shown to phosphorylate and inactivate Bim, we examined Bim expression in cell lines sensitive to combined treatment with Romidepsin and inhibitors. In the OVCAR5 cell line, which harbors a G12V KRAS mutation, we noted that Romidepsin induced Bim expression and that combined treatment with PD0325901 led to higher expression by western blot. The high levels of Bim expression were associated with increased poly ADP ribose polymerase cleavage. These data demonstrate the benefit of combining an HDI with MEK and AKT inhibitors in KRAS mutant cell lines. Romidepsin and MAPK pathway inhibitor combinations should be further evaluated in patients with mutant KRAS cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4708. doi:1538-7445.AM2012-4708
Richard Piekarz - One of the best experts on this subject based on the ideXlab platform.
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responses to Romidepsin in patients with cutaneous t cell lymphoma and prior treatment with systemic chemotherapy
Leukemia & Lymphoma, 2018Co-Authors: Madeleine Duvic, Richard Piekarz, Susan E Bates, Youn H Kim, Adam Lerner, Tadeusz Robak, Jurgen C Becker, Alexey Samtsov, Robin Eisch, William MccullochAbstract:Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas that typically present in the skin but can progress to systemic involvement. The optimal treatment for patients who relapse from or are refractory to systemic chemotherapy remains unclear. Romidepsin is a potent, class-I selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had ≥1 prior systemic therapy. Here, we present a subanalysis of two phase-2 trials (NCT00106431, NCT00007345) of Romidepsin in patients with CTCL who had prior treatment with systemic chemotherapy. Patients with prior chemotherapy were able to achieve durable responses to Romidepsin, and response rates were similar to those in patients who were chemotherapy naive. Overall, no new safety signals emerged in patients who had received prior chemotherapy. The data presented here suggest that Romidepsin is safe and effective in patients with CTCL who received prior systemic chemotherapy.
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electrocardiographic studies of Romidepsin demonstrate its safety and identify a potential role for katp channel
Clinical Cancer Research, 2013Co-Authors: Anne M Noonan, Robin A Eisch, David J Liewehr, Tristan M Sissung, David Venzon, Thomas P Flagg, Mark C Haigney, Seth M Steinberg, William D Figg, Richard PiekarzAbstract:Purpose: Romidepsin is a histone deacetylase inhibitor (HDI) approved for the treatment of both cutaneous and peripheral T-cell lymphoma (CTCL and PTCL). During development, a thorough assessment of cardiac toxicity was conducted. Experimental Design: A phase II single-agent nonrandomized study of Romidepsin was conducted in patients with CTCL or PTCL who had progressed after at least 1 prior systemic therapy. Results: Results for the first 42 patients enrolled on the NCI 1312 phase II study of Romidepsin in CTCL or PTCL showed no cardiac toxicity based on serial electrocardiograms (ECG), troponins, and MUGA scans/echocardiograms. The cardiac assessments reported herein confirm the safety of Romidepsin among 131 enrolled patients, while supporting a role for electrolyte replacement. Heart rate increased an average 11 bpm following Romidepsin infusion; there was no evidence of increased arrhythmia. Criteria for potassium/magnesium replacement were met before 55% of 1365 Romidepsin doses; an association with hypoalbuminemia was confirmed. We propose a mechanism for ST segment flattening and depression, the most common ECG abnormalities observed: HDI-induced alteration of the activity or expression of K ATP channels. In addition, examination of the variants of the active transporter of Romidepsin, ABCB1, showed a trend toward smaller heart rate changes in the peri-infusion period among wild-type than variant diplotypes. Conclusions: We conclude that in the context of appropriate attention to electrolyte levels, the data support the cardiac safety of Romidepsin. Clin Cancer Res; 19(11); 3095–104. ©2013 AACR .
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mapk pathway activation leads to bim loss and histone deacetylase inhibitor resistance rationale to combine Romidepsin with an mek inhibitor
Blood, 2013Co-Authors: Richard Piekarz, Arup R Chakraborty, Robert W Robey, Victoria Luchenko, Zhirong Zhan, Jeanpierre Gillet, Andrew V Kossenkov, Julia Wilkerson, Louise C ShoweAbstract:To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with Romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to Romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four- to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with Romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of Romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by Romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of Romidepsin with MEK inhibitors in clinical trials.
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abstract 3399 resistance to the histone deacetylase inhibitor Romidepsin is associated with degradation of bim following mapk pathway activation
Cancer Research, 2013Co-Authors: Arup R Chakraborty, Richard Piekarz, Victoria Luchenko, Zhirong Zhan, Jeanpierre Gillet, Andrew V Kossenkov, Rob Robey, Michael M Gottesman, Nathan L Collie, Louise C ShoweAbstract:Inhibition of histone deacetylase (HDAC) enzymes represents a promising therapeutic approach in clinical oncology, as aberrant gene expression and alterations in histone acetylation due to HDACs have been implicated in tumor development and progression. Even though several histone deacetylase inhibitors (HDIs) are currently in clinical trials, so far only the HDIs Romidepsin and vorinostat have been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL). During clinical trials with Romidepsin in CTCL, disease progression was noted in some patients who initially responded to therapy, while the disease in other patients did not respond to therapy suggesting that both de novo and acquired resistance to Romidepsin were observed. To identify molecular determinants of resistance, we selected HuT78 CTCL cells with Romidepsin in the presence of inhibitors of P-glycoprotein (Pgp) to prevent upregulation of Pgp as a mechanism of resistance. Resistant sublines were approximately 250- to 385-fold resistant to Romidepsin; the Pgp inhibitor tariquidar did not significantly reverse resistance. The sublines also exhibited resistance to apoptosis following treatment with the HDIs apicidin, belinostat, entinostat, panobinostat, and vorinostat. A custom gene-expression array detected elevated expression of insulin receptor (INSR) in Romidepsin resistant cells compared to parental cells. Immunoblot analysis of downstream effectors of the IR pathway demonstrated a 4- to 8-fold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation. Even though resistant cells did not respond to 48 h treatment with inhibitors of the insulin receptor, they exhibited exquisite sensitivity to treatment with as little as 1 nM of the MEK inhibitor PD0325901. Sensitivity to MEK inhibition in resistant cells was associated with restoration of the pro-apoptotic protein Bim. Combined treatment of Romidepsin with MEK inhibitors also significantly yielded greater apoptosis in resistant cells compared to Romidepsin and MEK inhibitor treatment alone. Gene expression analysis of circulating tumor samples obtained from patients with CTCL enrolled on the NCI 1312 Phase II Romidepsin study suggested interaction of Romidepsin with the MAPK pathway, indicated by altered expression of genes demonstrated to be under its control. These findings implicate activation of MEK as a resistance mechanism to Romidepsin, and suggest combination of Romidepsin with MEK inhibitors in clinical trials. Citation Format: Arup R. Chakraborty, Rob Robey, Zhirong Zhan, Victoria Luchenko, Michael Gottesman, Nathan Collie, Jean-Pierre Gillet, Richard Piekarz, Andrew Kossenkov, Louise Showe, Susan Bates. Resistance to the histone deacetylase inhibitor Romidepsin is associated with degradation of Bim following MAPK pathway activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3399. doi:10.1158/1538-7445.AM2013-3399
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abstract b9 activated mapk pathway mediates resistance to Romidepsin via bim degradation in Romidepsin selected hut 78 cells
Clinical Cancer Research, 2012Co-Authors: Arup R Chakraborty, Richard Piekarz, Robert W Robey, Victoria Luchenko, Jeanpierre Gillet, Michael M Gottesman, Nathan Collie, Susan E BatesAbstract:Acquired and intrinsic resistance to histone deacetylase inhibitors (HDIs), a new targeted group of anti-tumor agents, limits their clinical efficacy. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. To investigate molecular mechanisms of resistance to the HDI Romidepsin (Dp), we studied a cutaneous T-cell lymphoma (CTCL) cell line, HuT 78, independently selected in verapamil (Vp) or valspodar (PSC833) to prevent the emergence of P-glycoprotein (Pgp), a known resistance mechanism. The HuT 78 sublines DpVp 50 and DpP 75 display 100-200-fold resistance to Romidepsin, not due to Pgp expression. A custom-made Taqman low density gene expression array detected increased expression of insulin receptor (IR) in the resistant cells. Real-time PCR analysis confirmed the results of gene array and detected more than 50-fold upregulation of IR in the Romidepsin-selected cells compared to the parental cells. Increased phosphorylation (5- to 8- fold) of mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. While HuT 78 cells were insensitive to MEK inhibition, resistant cells were found to be exquisitely sensitive to MEK inhibition (IC50
Miles H Prince - One of the best experts on this subject based on the ideXlab platform.
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Romidepsin is effective and well tolerated in older patients with peripheral t cell lymphoma analysis of two phase ii trials
Leukemia & Lymphoma, 2017Co-Authors: Andrei R Shustov, Barbara Balser, Bertrand Coiffier, Barbara Pro, Lubomir Sokol, Robin Eisch, Steven M Horwitz, Julie Wolfson, Leslie Popplewell, Miles H PrinceAbstract:AbstractPeripheral T-cell lymphomas (PTCLs) are a rare group of lymphoid neoplasms with high relapse rates after initial therapy and poor prognosis. Most patients are aged ≥60 years and are often not candidates for aggressive salvage therapies. Romidepsin, a potent class I histone deacetylase inhibitor, has shown significant single-agent activity in relapsed/refractory PTCL. We evaluated the efficacy and tolerability of Romidepsin in elderly patients in this setting. Ninety-five patients aged ≥60 years were identified from 2 prospective phase 2 registration trials of Romidepsin, and comparative analyses were performed with younger patients from these trials. Response rates, progression-free survival, and overall survival were not statistically different for younger vs older patients. The toxicity profile in older and younger patients was similar in both trials. Romidepsin demonstrated similar efficacy and tolerability in younger and older patients and presents an attractive treatment option for relapsed/r...
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responses to Romidepsin by line of therapy in patients with relapsed or refractory peripheral t cell lymphoma
Cancer Medicine, 2017Co-Authors: Francine M Foss, Barbara Pro, Miles H Prince, Lubomir Sokol, Dolores Caballero, Steven M Horwitz, Bertrand CoiffierAbstract:Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas typically associated with poor prognosis. Most patients with PTCL receive chemotherapy as first-line treatment, but many experience rapid relapse. For patients with relapsed/refractory PTCL, responses to treatment and long-term outcomes tend to worsen with increasing lines of therapy. Romidepsin is a potent class I histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of PTCL in patients who have received ≥1 prior therapy. A pivotal phase 2 trial of Romidepsin in patients with relapsed/refractory PTCL demonstrated an objective response rate of 25% (33/130), including 15% with confirmed/unconfirmed complete response, and a median duration of response of 28 months. In the analysis presented herein, Romidepsin was shown to have similar responses and long-term outcomes in patients with 1, 2, and ≥3 prior lines of treatment, including in patients with disease refractory to the last prior therapy. Although adverse events increased with increasing lines of treatment, the rate of dose modifications and discontinuations due to adverse events was not significantly different. These data support the use of Romidepsin as salvage treatment for PTCL irrespective of the number of prior therapies.
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Romidepsin for the treatment of relapsed refractory peripheral t cell lymphoma prolonged stable disease provides clinical benefits for patients in the pivotal trial
Journal of Hematology & Oncology, 2016Co-Authors: Francine M Foss, Barbara Balser, Barbara Pro, Miles H Prince, Lubomir Sokol, Steven M Horwitz, Julie Wolfson, Bertrand CoiffierAbstract:Achievement of durable responses in patients with relapsed/refractory peripheral T cell lymphoma (PTCL) is challenging with current therapies, and there are few data regarding the potential benefits of continuing treatment in patients with the best response of stable disease (SD). Histone deacetylase inhibitors are a novel class of drugs with activity in T cell malignancies. Romidepsin was approved by the US Food and Drug Administration for the treatment of relapsed/refractory PTCL based on a pivotal trial demonstrating an objective response rate of 25 % (33/130), including 15 % with confirmed/unconfirmed complete response and a median duration of response of 28 months. Our objective was to further study the clinical benefits of Romidepsin in patients that had the best response of SD. Patients with PTCL relapsed/refractory to ≥1 prior therapy were treated with the approved dose of 14 mg/m2 Romidepsin on days 1, 8, and 15 of six 28-day cycles; patients with SD or response after cycle 6 were allowed to continue on study until progression. By protocol amendment, patients treated for ≥12 cycles could receive maintenance dosing twice per cycle; after cycle 24, dosing could be further reduced to once per cycle in those who had received maintenance dosing for ≥6 months. Of the 32 patients (25 %) with the best response of SD, 22 had SD for ≥90 days (SD90; cycle 4 response assessment). The longest SD was >3 years in a patient who received maintenance dosing of 14 mg/m2 on days 1 and 15 beginning in cycle 13. Patients with the best response of SD90 or partial response achieved similar overall and progression-free survival. Prolonged dosing of Romidepsin was well tolerated. We concluded that patients who achieve SD may consider continuing treatment because the clinical benefits of Romidepsin may extend beyond objective responses. NCT00426764
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Romidepsin in peripheral and cutaneous t cell lymphoma mechanistic implications from clinical and correlative data
British Journal of Haematology, 2015Co-Authors: Susan E Bates, Miles H Prince, Robin Eisch, Steven L Allen, Mark Kirschbaum, Maria L Turner, Alexander Ling, Douglas R Rosing, Stefania Pittaluga, Jasmine ZainAbstract:Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving Romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to disease regression. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of Romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.
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Romidepsin in peripheral and cutaneous t cell lymphoma mechanistic implications from clinical and correlative data
British Journal of Haematology, 2015Co-Authors: Susan E Bates, Miles H Prince, Robin Eisch, Steven L Allen, Mark Kirschbaum, Maria L Turner, Alexander Ling, Douglas R Rosing, Stefania Pittaluga, Jasmine ZainAbstract:Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving Romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of Romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.
Robert W Robey - One of the best experts on this subject based on the ideXlab platform.
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mapk pathway activation leads to bim loss and histone deacetylase inhibitor resistance rationale to combine Romidepsin with an mek inhibitor
Blood, 2013Co-Authors: Richard Piekarz, Arup R Chakraborty, Robert W Robey, Victoria Luchenko, Zhirong Zhan, Jeanpierre Gillet, Andrew V Kossenkov, Julia Wilkerson, Louise C ShoweAbstract:To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with Romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to Romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four- to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with Romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of Romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by Romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of Romidepsin with MEK inhibitors in clinical trials.
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abstract b9 activated mapk pathway mediates resistance to Romidepsin via bim degradation in Romidepsin selected hut 78 cells
Clinical Cancer Research, 2012Co-Authors: Arup R Chakraborty, Richard Piekarz, Robert W Robey, Victoria Luchenko, Jeanpierre Gillet, Michael M Gottesman, Nathan Collie, Susan E BatesAbstract:Acquired and intrinsic resistance to histone deacetylase inhibitors (HDIs), a new targeted group of anti-tumor agents, limits their clinical efficacy. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. To investigate molecular mechanisms of resistance to the HDI Romidepsin (Dp), we studied a cutaneous T-cell lymphoma (CTCL) cell line, HuT 78, independently selected in verapamil (Vp) or valspodar (PSC833) to prevent the emergence of P-glycoprotein (Pgp), a known resistance mechanism. The HuT 78 sublines DpVp 50 and DpP 75 display 100-200-fold resistance to Romidepsin, not due to Pgp expression. A custom-made Taqman low density gene expression array detected increased expression of insulin receptor (IR) in the resistant cells. Real-time PCR analysis confirmed the results of gene array and detected more than 50-fold upregulation of IR in the Romidepsin-selected cells compared to the parental cells. Increased phosphorylation (5- to 8- fold) of mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. While HuT 78 cells were insensitive to MEK inhibition, resistant cells were found to be exquisitely sensitive to MEK inhibition (IC50
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abstract 4708 short term Romidepsin treatment combined with mitogen activated protein kinase and phosphatidylinositol 3 kinase inhibition causes increased bim expression and cell death in kras mutant cell lines
Cancer Research, 2012Co-Authors: Julian C Bahr, Robert W Robey, Victoria Luchenko, Arup Chakraborty, Susan E BatesAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Romidepsin (FK228) is a histone deacetylase inhibitor (HDI) that modulates chromatin and activates apoptotic pathways in vitro. Clinical efficacy observed in peripheral and cutaneous T-cell lymphoma has not been replicated in solid tumors, as for other HDIs. We thus sought drug combinations that might improve the activity of Romidepsin in solid tumors. Mutations in KRAS induce the mitogen activated protein kinase pathway (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathway. Laboratory data have suggested that activated MEK or AKT can confer resistance to HDIs. To determine if mitogen-activated protein kinase kinase (MEK) or AKT inhibitors could increase sensitivity to Romidepsin, we measured cell death by annexin assay in a panel of 20 cell lines, nine KRAS mutants and eleven KRAS wild-type (WT). Cells were exposed to 25 ng/ml Romidepsin for 6 h in the presence of 250 nM MEK inhibitor PD0325901 and/or 1 µM AKT inhibitor MK2206, after which Romidepsin was removed and cells were incubated with the inhibitors alone for an additional 42 h. Among the 20 solid tumor cell lines examined, those harboring a KRAS mutation had a higher percentage of cell death than lines with WT KRAS when treated with the PD0325901/Romidepsin combination (46.1±18% vs. 21.6±7.6% respectively, p-value .0057), the MK2206/Romidepsin combination (43.8±15.8% vs. 28.6±13.6%, respectively, p-value .0470), or the PD0325901/MK2206/Romidepsin combination (66.5±14.8% vs. 35.0±18.8%, respectively, p-value .0008). There was no statistically significant difference (p-value > .05) in cell death between KRAS and WT cell lines treated with any of the compounds alone. As expression of the pro-apoptotic protein Bim has been associated with Romidepsin-mediated cell death, and as the MAPK pathway has been shown to phosphorylate and inactivate Bim, we examined Bim expression in cell lines sensitive to combined treatment with Romidepsin and inhibitors. In the OVCAR5 cell line, which harbors a G12V KRAS mutation, we noted that Romidepsin induced Bim expression and that combined treatment with PD0325901 led to higher expression by western blot. The high levels of Bim expression were associated with increased poly ADP ribose polymerase cleavage. These data demonstrate the benefit of combining an HDI with MEK and AKT inhibitors in KRAS mutant cell lines. Romidepsin and MAPK pathway inhibitor combinations should be further evaluated in patients with mutant KRAS cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4708. doi:1538-7445.AM2012-4708
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abstract 4709 combined mitogen activated protein kinase pathway inhibition with short term Romidepsin treatment induces proapoptotic bim and cell death in braf mutant cancers
Cancer Research, 2012Co-Authors: Robert W Robey, Richard Piekarz, Victoria Luchenko, Julian C Bahr, Arup Chakraborty, Alexandra S Zimmer, Susan E BatesAbstract:Solid tumor trials with histone deacetylase inhibitors (HDIs) have been largely disappointing. We recently characterized a Romidepsin-resistant T-cell lymphoma cell line that was found to have activation of the mitogen-activated protein kinase (MAPK) pathway, leading to subsequent phosphorylation and degradation of the proapoptotic protein Bim, suggesting that activation of this pathway may also confer resistance to Romidepsin and other HDIs. The V600E BRAF mutation has been found in approximately 60% of melanomas and approximately 15% of colon cancers and leads to constitutive activation of the MAPK pathway. We thus hypothesized that combined treatment with Romidepsin and BRAF or mitogen-activated protein kinase kinase (MEK) inhibitors may be effective in cancers that harbor the V600E BRAF mutation. To more closely simulate clinical administration of Romidepsin, 11 V600E BRAF mutant cell lines (8 melanomas and 3 colorectal cancers) were exposed to 25 ng/ml Romidepsin for 6 h after which Romidepsin was removed, cells were incubated in fresh medium for an additional 42 h and subsequently apoptosis was measured by Annexin V and propidium iodide staining. Of the 11 cell lines, 10 exhibited significantly higher annexin staining after short-term Romidepsin treatment (control 7.1% ± 3.8% vs. treated 34.7% ± 17.8%, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4709. doi:1538-7445.AM2012-4709
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abstract 4708 short term Romidepsin treatment combined with mitogen activated protein kinase and phosphatidylinositol 3 kinase inhibition causes increased bim expression and cell death in kras mutant cell lines
Cancer Research, 2012Co-Authors: Julian C Bahr, Robert W Robey, Victoria Luchenko, Arup K Chakraborty, Susan E BatesAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Romidepsin (FK228) is a histone deacetylase inhibitor (HDI) that modulates chromatin and activates apoptotic pathways in vitro. Clinical efficacy observed in peripheral and cutaneous T-cell lymphoma has not been replicated in solid tumors, as for other HDIs. We thus sought drug combinations that might improve the activity of Romidepsin in solid tumors. Mutations in KRAS induce the mitogen activated protein kinase pathway (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathway. Laboratory data have suggested that activated MEK or AKT can confer resistance to HDIs. To determine if mitogen-activated protein kinase kinase (MEK) or AKT inhibitors could increase sensitivity to Romidepsin, we measured cell death by annexin assay in a panel of 20 cell lines, nine KRAS mutants and eleven KRAS wild-type (WT). Cells were exposed to 25 ng/ml Romidepsin for 6 h in the presence of 250 nM MEK inhibitor PD0325901 and/or 1 µM AKT inhibitor MK2206, after which Romidepsin was removed and cells were incubated with the inhibitors alone for an additional 42 h. Among the 20 solid tumor cell lines examined, those harboring a KRAS mutation had a higher percentage of cell death than lines with WT KRAS when treated with the PD0325901/Romidepsin combination (46.1±18% vs. 21.6±7.6% respectively, p-value .0057), the MK2206/Romidepsin combination (43.8±15.8% vs. 28.6±13.6%, respectively, p-value .0470), or the PD0325901/MK2206/Romidepsin combination (66.5±14.8% vs. 35.0±18.8%, respectively, p-value .0008). There was no statistically significant difference (p-value > .05) in cell death between KRAS and WT cell lines treated with any of the compounds alone. As expression of the pro-apoptotic protein Bim has been associated with Romidepsin-mediated cell death, and as the MAPK pathway has been shown to phosphorylate and inactivate Bim, we examined Bim expression in cell lines sensitive to combined treatment with Romidepsin and inhibitors. In the OVCAR5 cell line, which harbors a G12V KRAS mutation, we noted that Romidepsin induced Bim expression and that combined treatment with PD0325901 led to higher expression by western blot. The high levels of Bim expression were associated with increased poly ADP ribose polymerase cleavage. These data demonstrate the benefit of combining an HDI with MEK and AKT inhibitors in KRAS mutant cell lines. Romidepsin and MAPK pathway inhibitor combinations should be further evaluated in patients with mutant KRAS cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4708. doi:1538-7445.AM2012-4708
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phase i trial of a new schedule of Romidepsin in patients with advanced cancers
Clinical Cancer Research, 2013Co-Authors: Laleh Amirikordestani, David Venzon, Victoria Luchenko, Robin Frye, Cody J Peer, Kambiz Ghafourian, James C Reynolds, Deb Draper, Sue Woo, John J WrightAbstract:Purpose: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 Romidepsin schedule was evaluated. A secondary objective was to assess the effect of Romidepsin on radioactive iodine (RAI) uptake in thyroid cancers. Experimental Design: Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes. Results: Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m2 on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors–defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21–112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases. Conclusions: A Romidepsin dose of 7 mg/m2 administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with Romidepsin alone, this schedule may be useful for developing combination studies in solid tumors. Clin Cancer Res; 19(16); 4499–507. ©2013 AACR .
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mapk pathway activation leads to bim loss and histone deacetylase inhibitor resistance rationale to combine Romidepsin with an mek inhibitor
Blood, 2013Co-Authors: Richard Piekarz, Arup R Chakraborty, Robert W Robey, Victoria Luchenko, Zhirong Zhan, Jeanpierre Gillet, Andrew V Kossenkov, Julia Wilkerson, Louise C ShoweAbstract:To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with Romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to Romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four- to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with Romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of Romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by Romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of Romidepsin with MEK inhibitors in clinical trials.
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abstract 3399 resistance to the histone deacetylase inhibitor Romidepsin is associated with degradation of bim following mapk pathway activation
Cancer Research, 2013Co-Authors: Arup R Chakraborty, Richard Piekarz, Victoria Luchenko, Zhirong Zhan, Jeanpierre Gillet, Andrew V Kossenkov, Rob Robey, Michael M Gottesman, Nathan L Collie, Louise C ShoweAbstract:Inhibition of histone deacetylase (HDAC) enzymes represents a promising therapeutic approach in clinical oncology, as aberrant gene expression and alterations in histone acetylation due to HDACs have been implicated in tumor development and progression. Even though several histone deacetylase inhibitors (HDIs) are currently in clinical trials, so far only the HDIs Romidepsin and vorinostat have been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL). During clinical trials with Romidepsin in CTCL, disease progression was noted in some patients who initially responded to therapy, while the disease in other patients did not respond to therapy suggesting that both de novo and acquired resistance to Romidepsin were observed. To identify molecular determinants of resistance, we selected HuT78 CTCL cells with Romidepsin in the presence of inhibitors of P-glycoprotein (Pgp) to prevent upregulation of Pgp as a mechanism of resistance. Resistant sublines were approximately 250- to 385-fold resistant to Romidepsin; the Pgp inhibitor tariquidar did not significantly reverse resistance. The sublines also exhibited resistance to apoptosis following treatment with the HDIs apicidin, belinostat, entinostat, panobinostat, and vorinostat. A custom gene-expression array detected elevated expression of insulin receptor (INSR) in Romidepsin resistant cells compared to parental cells. Immunoblot analysis of downstream effectors of the IR pathway demonstrated a 4- to 8-fold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation. Even though resistant cells did not respond to 48 h treatment with inhibitors of the insulin receptor, they exhibited exquisite sensitivity to treatment with as little as 1 nM of the MEK inhibitor PD0325901. Sensitivity to MEK inhibition in resistant cells was associated with restoration of the pro-apoptotic protein Bim. Combined treatment of Romidepsin with MEK inhibitors also significantly yielded greater apoptosis in resistant cells compared to Romidepsin and MEK inhibitor treatment alone. Gene expression analysis of circulating tumor samples obtained from patients with CTCL enrolled on the NCI 1312 Phase II Romidepsin study suggested interaction of Romidepsin with the MAPK pathway, indicated by altered expression of genes demonstrated to be under its control. These findings implicate activation of MEK as a resistance mechanism to Romidepsin, and suggest combination of Romidepsin with MEK inhibitors in clinical trials. Citation Format: Arup R. Chakraborty, Rob Robey, Zhirong Zhan, Victoria Luchenko, Michael Gottesman, Nathan Collie, Jean-Pierre Gillet, Richard Piekarz, Andrew Kossenkov, Louise Showe, Susan Bates. Resistance to the histone deacetylase inhibitor Romidepsin is associated with degradation of Bim following MAPK pathway activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3399. doi:10.1158/1538-7445.AM2013-3399
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abstract b9 activated mapk pathway mediates resistance to Romidepsin via bim degradation in Romidepsin selected hut 78 cells
Clinical Cancer Research, 2012Co-Authors: Arup R Chakraborty, Richard Piekarz, Robert W Robey, Victoria Luchenko, Jeanpierre Gillet, Michael M Gottesman, Nathan Collie, Susan E BatesAbstract:Acquired and intrinsic resistance to histone deacetylase inhibitors (HDIs), a new targeted group of anti-tumor agents, limits their clinical efficacy. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. To investigate molecular mechanisms of resistance to the HDI Romidepsin (Dp), we studied a cutaneous T-cell lymphoma (CTCL) cell line, HuT 78, independently selected in verapamil (Vp) or valspodar (PSC833) to prevent the emergence of P-glycoprotein (Pgp), a known resistance mechanism. The HuT 78 sublines DpVp 50 and DpP 75 display 100-200-fold resistance to Romidepsin, not due to Pgp expression. A custom-made Taqman low density gene expression array detected increased expression of insulin receptor (IR) in the resistant cells. Real-time PCR analysis confirmed the results of gene array and detected more than 50-fold upregulation of IR in the Romidepsin-selected cells compared to the parental cells. Increased phosphorylation (5- to 8- fold) of mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. While HuT 78 cells were insensitive to MEK inhibition, resistant cells were found to be exquisitely sensitive to MEK inhibition (IC50
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abstract 4708 short term Romidepsin treatment combined with mitogen activated protein kinase and phosphatidylinositol 3 kinase inhibition causes increased bim expression and cell death in kras mutant cell lines
Cancer Research, 2012Co-Authors: Julian C Bahr, Robert W Robey, Victoria Luchenko, Arup Chakraborty, Susan E BatesAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Romidepsin (FK228) is a histone deacetylase inhibitor (HDI) that modulates chromatin and activates apoptotic pathways in vitro. Clinical efficacy observed in peripheral and cutaneous T-cell lymphoma has not been replicated in solid tumors, as for other HDIs. We thus sought drug combinations that might improve the activity of Romidepsin in solid tumors. Mutations in KRAS induce the mitogen activated protein kinase pathway (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathway. Laboratory data have suggested that activated MEK or AKT can confer resistance to HDIs. To determine if mitogen-activated protein kinase kinase (MEK) or AKT inhibitors could increase sensitivity to Romidepsin, we measured cell death by annexin assay in a panel of 20 cell lines, nine KRAS mutants and eleven KRAS wild-type (WT). Cells were exposed to 25 ng/ml Romidepsin for 6 h in the presence of 250 nM MEK inhibitor PD0325901 and/or 1 µM AKT inhibitor MK2206, after which Romidepsin was removed and cells were incubated with the inhibitors alone for an additional 42 h. Among the 20 solid tumor cell lines examined, those harboring a KRAS mutation had a higher percentage of cell death than lines with WT KRAS when treated with the PD0325901/Romidepsin combination (46.1±18% vs. 21.6±7.6% respectively, p-value .0057), the MK2206/Romidepsin combination (43.8±15.8% vs. 28.6±13.6%, respectively, p-value .0470), or the PD0325901/MK2206/Romidepsin combination (66.5±14.8% vs. 35.0±18.8%, respectively, p-value .0008). There was no statistically significant difference (p-value > .05) in cell death between KRAS and WT cell lines treated with any of the compounds alone. As expression of the pro-apoptotic protein Bim has been associated with Romidepsin-mediated cell death, and as the MAPK pathway has been shown to phosphorylate and inactivate Bim, we examined Bim expression in cell lines sensitive to combined treatment with Romidepsin and inhibitors. In the OVCAR5 cell line, which harbors a G12V KRAS mutation, we noted that Romidepsin induced Bim expression and that combined treatment with PD0325901 led to higher expression by western blot. The high levels of Bim expression were associated with increased poly ADP ribose polymerase cleavage. These data demonstrate the benefit of combining an HDI with MEK and AKT inhibitors in KRAS mutant cell lines. Romidepsin and MAPK pathway inhibitor combinations should be further evaluated in patients with mutant KRAS cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4708. doi:1538-7445.AM2012-4708
