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Richard D. Carvajal - One of the best experts on this subject based on the ideXlab platform.
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efficacy safety and tolerability of approved combination braf and MEK Inhibitor regimens for braf mutant melanoma
Cancers, 2019Co-Authors: Omid Hamid, Lance C Cowey, Michelle Offner, Mark B Faries, Richard D. CarvajalAbstract:No head-to-head studies exist comparing BRAF Inhibitor/MEK Inhibitor (BRAFi/MEKi) combination treatments for BRAF-mutant melanoma. A side-by-side analysis of randomized phase III trials is presented that evaluated dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib. The baseline characteristics, efficacy, and safety were compared: COMBI-v (dabrafenib/trametinib versus vemurafenib); coBRIM (vemurafenib/cobimetinib versus vemurafenib); and COLUMBUS (encorafenib/binimetinib versus encorafenib and vemurafenib). Vemurafenib was the control arm in all studies. The data sources included literature databases, European public assessment reports, U.S. Food and Drug Administration review documents, and prescribing information. The baseline characteristics were similar, except for coBRIM, which had a higher proportion of patients with elevated lactate dehydrogenase (LDH) levels. The median progression-free survival (PFS) and overall response rate (ORR) were similar across the trials, although numerically higher values were observed with encorafenib/binimetinib. In contrast, the median overall survival (OS) was numerically longer with encorafenib/binimetinib (33.6 months) compared to dabrafenib/trametinib (25.6 months) and vemurafenib/cobimetinib (22.3 months). Among vemurafenib arms, PFS, ORR, and OS were similar, despite variations in the baseline LDH. Each combination displayed a unique safety profile, with higher incidences of pyrexia with dabrafenib/trametinib and photosensitivity reactions with vemurafenib/cobimetinib. This analysis of BRAFi/MEKi combinations for BRAF-mutant melanoma, while limited as not a direct head-to-head clinical trial, highlights the differences in tolerability and efficacy that may be useful for therapeutic decision making.
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Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells
Molecular cancer therapeutics, 2014Co-Authors: Grazia Ambrosini, Raya Khanin, Richard D. Carvajal, Gary K SchwartzAbstract:The majority of uveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11, with consequent activation of the MAPK pathway. Selective MEK Inhibitors, such as selumetinib, have shown clinical benefit in uveal melanoma. However, mechanisms of drug resistance limit their efficacy in some patients. Analysis of MEK Inhibitor–resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity. This effect was mediated by the RNA helicase DDX43, which was remarkably overexpressed in these cells. Depletion of DDX43 in MEK Inhibitor–resistant cells decreased RAS proteins and inhibited ERK and AKT pathways. On the contrary, ectopic expression of DDX43 in parental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition. Similar to DDX43 depletion, downregulation of KRAS, HRAS, and NRAS inhibited downstream pathways in the resistant cells, overcoming mutant GNAQ signaling. We also analyzed the expression of DDX43 in liver metastases of patients with uveal melanoma by RT-PCR, and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy. In conclusion, DDX43 induces RAS protein expression and signaling, mediating a novel mechanism of MEK Inhibitor resistance. The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this disease. Mol Cancer Ther; 13(8); 2073–80. ©2014 AACR .
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abstract 2284 phase ii trial of MEK Inhibitor selumetinib azd6244 in patients with brafv600e k or nras mutated melanoma
Cancer Research, 2013Co-Authors: Federica Catalanotti, David B Solit, Melissa Pulitzer, Michael F Berger, Sasinya N Scott, Tunc Iyriboz, Mario E Lacouture, Katherine S Panageas, Jedd D Wolchok, Richard D. CarvajalAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Our pre-clinical in vitro data suggested that all BRAF-mutated cell lines, and some NRAS-mutated melanoma are sensitive to MEK inhibition. BRAFwt/NRASwt were uniformly resistant. Among the sensitive cell lines, those with enhanced activation of the PI3K/AKT pathway did not undergo apoptosis. This is consistent with a recent phase II trial with Selumetinib, an allosteric MEK Inhibitor, which showed a 6% response rate in unselected melanoma patients. Retrospectively, 5 of 6 of the responders were found to harbor BRAFV600E mutations. We hypothesized that treatment of BRAF-mutated or NRAS-mutated melanomas with Selumetinib will induce clinical responses only in the subset of tumors in which the PI3K/AKT pathway is not activated. In this phase II trial, melanoma patients with either BRAF or NRAS mutation were stratified based on phospho-AKT (pAKT) expression (high vs. low), as measured by immunohistochemistry staining of pre-treatment tumor specimens. Patients were treated with Selumetinib 75 mg p.o. daily in 28-day cycles. We found that the incidence of high pAKT melanoma tumors was about 4 times higher than low pAKT tumors. None of the 10 patients in the high pAKT cohort responded, although 4 patients showed stable disease for ≥4 months. This cohort was closed to further accrual. In contrast, in the low pAKT group, 1 patient had a true partial response (PR) and 2 others had near PRs. One of these patients had to discontinue treatment due to toxicity; the other had his remaining tumor resected. This cohort was closed due to slow patient accrual. We used an exon capture, next-generation sequencing assay to define the mutational status of 230 cancer associated genes in pre-treatment tumors, derived from patients belonging to both cohorts. The assay detects point mutations, small indels and copy number alterations. Among the two low pAKT patients who were resistant to MEK inhibition, one had a mutation in MAP2K1 that encodes for a K57N mutation in helix A of MEK1. We speculate that this is an activating mutation, since a missense mutation in the amino acid just proximal (Q56P) was previously shown to be highly activating. The other non-responding patient in the low pAKT cohort had an activating mutation in EGFR. Both of these could drive increased activation of the MAPK pathway, thus explaining the resistance to the drug. We conclude that future trials with MEK Inhibitors in melanoma should exclude patients with high pAKT tumors. The occurrence of complex genetic changes in melanoma requires studies to better stratify the patients according the prediction of response to MEK Inhibitors. Citation Format: Federica Catalanotti, David B. Solit, Melissa P. Pulitzer, Michael F. Berger, Sasinya N. Scott, Tunc Iyriboz, Mario E. Lacouture, Katherine S. Panageas, Jedd D. Wolchok, Richard D. Carvajal, Gary K. Schwartz, Neal Rosen, Paul B. Chapman. Phase II trial of MEK Inhibitor selumetinib (AZD6244) in patients with BRAFV600E/K- or NRAS-mutated melanoma. [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 2284. doi:10.1158/1538-7445.AM2013-2284
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phase ii trial of MEK Inhibitor selumetinib azd6244 arry 142886 in patients with brafv600e k mutated melanoma
Clinical Cancer Research, 2013Co-Authors: Federica Catalanotti, David B Solit, Melissa Pulitzer, Michael F Berger, Sasinya N Scott, Tunc Iyriboz, Mario E Lacouture, Katherine S Panageas, Jedd D Wolchok, Richard D. CarvajalAbstract:Purpose: Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK Inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated. Experimental Design: We conducted a phase II trial in patients with melanoma whose tumors harbored a BRAF mutation. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg per os twice daily. Pretreatment tumors were also analyzed for genetic changes in 230 genes of interest using an exon-capture approach. Results: The high pAKT cohort was closed after no responses were seen in the first 10 patients. The incidence of low pAKT melanoma tumors was low (∼25% of melanomas tested) and this cohort was eventually closed because of poor accrual. However, among the five patients with melanoma accrued in the low pAKT cohort, there was one partial response (PR). Two other patients had near PRs before undergoing surgical resection of residual disease (one patient) or discontinuation of treatment due to toxicity (one patient). Among the two nonresponding, low pAKT patients with melanoma, co-mutations in MAP2K1 , NF1 , and/or EGFR were detected. Conclusions: Tumor regression was seen in three of five patients with BRAF-mutated, low pAKT melanomas; no responses were seen in the high pAKT cohort. These results provide rationale for co-targeting MEK and PI3K/AKT in patients with BRAF mutant melanoma whose tumors express high pAKT. However, the complexity of genetic changes in melanoma indicates that additional genetic information will be needed for optimal selection of patients likely to respond to MEK Inhibitors. Clin Cancer Res; 19(8); 2257–64. ©2013 AACR .
Chandra Bartholomeusz - One of the best experts on this subject based on the ideXlab platform.
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abstract p5 03 06 overcoming MEK Inhibitor resistance in triple negative breast cancer by targeting myeloid cell leukemia 1 mcl1 an anti apoptotic protein
Cancer Research, 2019Co-Authors: Maria Gagliardi, Mary Kathryn Pitner, Gaurav B Chauhan, Lakesla R Iles, Lajos Pusztai, Debu Tripathy, Geoffrey Bartholomeusz, Chandra BartholomeuszAbstract:Background: Triple-negative breast cancer (TNBC), which affects over 170 000 women worldwide every year, is considered the most arduous to treat subtype of breast cancer. With no targeted therapy, high rates of drug resistance and rapid metastasis, TNBC carries a poor prognosis. The MEK-ERK-MAPK signaling cascade is known to play a role in numerous cancers. Despite the lack of activating Ras/MAPK mutations in breast cancer, transcriptional signatures of this pathway are prevalent in TNBC. Our previous work showed that TNBC patients with tumors overexpressing ERK2 had a lower overall survival rate than did patients with low-ERK2-expressing tumors. MEK Inhibitors selumetinib (AZD6244) and pimasertib (AS703026) are active in preclinical models, but not as single agents in the clinic. Using a synthetic lethal siRNA screen, we identified myeloid cell leukemia-1 ( MCL1 ) as a potential contributor to selumetinib resistance. Mcl-1 is an anti-apoptotic protein that is highly amplified in numerous human cancers. It is associated with cell immortalization, transformation, and chemoresistance. Patients with TNBC tumors expressing high levels of Mcl-1 have lower overall survival and distant-metastasis-free survival rates. We hypothesized that Mcl-1 promotes MEK Inhibitor resistance in TNBC. Methods/Results: To model MEK Inhibitor resistance, we established selumetinib- and pimasertib-resistant clones of SUM-149 and MDA-MB-231 TNBC cells by continuous exposure to increasing concentrations of Inhibitors over a six month period. We confirmed the onset of MEK resistance by demonstrating that resistant cells, in comparison to the parental cells, exhibited no change in cell proliferation upon treatment with the MEK Inhibitors. Resistant cells also displayed more effective cell migration and mammosphere formation than parental cells, suggesting a higher fraction of tumor-initiating cells. We found Mcl-1 to be highly expressed in 83% (15 of 18) of TNBC cell lines but only 30% (3 of 10) of other breast cancer cell lines. Resistant cells had higher levels of Mcl-1 than did parental cells. To determine whether Mcl-1 is required for MEK sensitivity, we treated parental and resistant cells with either selumetinib or pimasertib together with S63845, a highly specific Mcl-1 Inhibitor. The Mcl-1 Inhibitor restored MEK sensitivity in both resistant cell lines. After treatment with the Mcl-1 Inhibitor, the resistant SUM-149 and MDA-MB-231 cells had similar cell proliferation rates to those of their parental counterparts. Similar studies were done using an siRNA against Mcl-1. Conclusion: Our data demonstrate that Mcl-1 may promote TNBC resistance to MEK Inhibitors and that Mcl-1 is a promising target for combination therapy. We will continue to explore the mechanisms of MEK Inhibitor resistance by screening for additional genes/pathways involved. Our long-term goal is to design rational combination approaches to counteract the emergence of resistance by using novel molecularly targeted therapeutics. Citation Format: Gagliardi M, Chauhan G, Pitner MK, Iles L, Qi Y, Pusztai L, Tripathy D, Bartholomeusz G, Bartholomeusz C. Overcoming MEK Inhibitor resistance in triple-negative breast cancer by targeting myeloid cell leukemia-1 ( MCL1 ), an anti-apoptotic protein [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-06.
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MEK Inhibitor selumetinib (AZD6244; ARRY-142886) prevents lung metastasis in a triple-negative breast cancer xenograft model
Molecular cancer therapeutics, 2015Co-Authors: Chandra Bartholomeusz, Paul D. Smith, Ali Dadbin, Hitomi Saso, Kimie Kondo, Jangsoon Lee, Xuemei Xie, Mary Kathryn Pitner, Kevin N. Dalby, Naoto T. UenoAbstract:Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with extracellular signal-regulated kinase 2 (ERK2)-overexpressing tumors were at higher risk of death than those with low-ERK2-expressing tumors (hazard ratio, 2.76; 95% confidence interval, 1.19-6.41). The MAPK pathway has been shown to be a marker of breast cancer metastasis, but has not been explored as a potential therapeutic target for preventing TNBC metastasis. Interestingly, when we treated TNBC cells with the allosteric MEK Inhibitor selumetinib, cell viability was not reduced in two-dimensional culture. However, in three-dimensional culture, selumetinib changed the mesenchymal phenotype of TNBC cells to an epithelial phenotype. Cells that undergo epithelial-mesenchymal transition (EMT) are thought to contribute to the metastatic process. EMT leads to generation of mesenchymal-like breast cancer cells with stem cell-like characteristics and a CD44(+)CD24(-/low) expression pattern. We tested the hypothesis that targeted inhibition of the MAPK pathway by selumetinib inhibits acquisition of the breast cancer stem cell phenotype and prevents lung metastasis of TNBC. TNBC cells treated with selumetinib showed inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P < 0.005), and decreases in the CD44(+)CD24(-/low) fraction, ALDH1 activity, and mammosphere-forming efficiency. Mice treated with selumetinib formed significantly fewer lung metastases than control mice injected with vehicle (P < 0.05). Our data demonstrate that MEK Inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis in certain cases in which tumors are MAPK dependent.
Naoto T. Ueno - One of the best experts on this subject based on the ideXlab platform.
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MEK Inhibitor selumetinib (AZD6244; ARRY-142886) prevents lung metastasis in a triple-negative breast cancer xenograft model
Molecular cancer therapeutics, 2015Co-Authors: Chandra Bartholomeusz, Paul D. Smith, Ali Dadbin, Hitomi Saso, Kimie Kondo, Jangsoon Lee, Xuemei Xie, Mary Kathryn Pitner, Kevin N. Dalby, Naoto T. UenoAbstract:Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with extracellular signal-regulated kinase 2 (ERK2)-overexpressing tumors were at higher risk of death than those with low-ERK2-expressing tumors (hazard ratio, 2.76; 95% confidence interval, 1.19-6.41). The MAPK pathway has been shown to be a marker of breast cancer metastasis, but has not been explored as a potential therapeutic target for preventing TNBC metastasis. Interestingly, when we treated TNBC cells with the allosteric MEK Inhibitor selumetinib, cell viability was not reduced in two-dimensional culture. However, in three-dimensional culture, selumetinib changed the mesenchymal phenotype of TNBC cells to an epithelial phenotype. Cells that undergo epithelial-mesenchymal transition (EMT) are thought to contribute to the metastatic process. EMT leads to generation of mesenchymal-like breast cancer cells with stem cell-like characteristics and a CD44(+)CD24(-/low) expression pattern. We tested the hypothesis that targeted inhibition of the MAPK pathway by selumetinib inhibits acquisition of the breast cancer stem cell phenotype and prevents lung metastasis of TNBC. TNBC cells treated with selumetinib showed inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P < 0.005), and decreases in the CD44(+)CD24(-/low) fraction, ALDH1 activity, and mammosphere-forming efficiency. Mice treated with selumetinib formed significantly fewer lung metastases than control mice injected with vehicle (P < 0.05). Our data demonstrate that MEK Inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis in certain cases in which tumors are MAPK dependent.
Mary Kathryn Pitner - One of the best experts on this subject based on the ideXlab platform.
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abstract p5 03 06 overcoming MEK Inhibitor resistance in triple negative breast cancer by targeting myeloid cell leukemia 1 mcl1 an anti apoptotic protein
Cancer Research, 2019Co-Authors: Maria Gagliardi, Mary Kathryn Pitner, Gaurav B Chauhan, Lakesla R Iles, Lajos Pusztai, Debu Tripathy, Geoffrey Bartholomeusz, Chandra BartholomeuszAbstract:Background: Triple-negative breast cancer (TNBC), which affects over 170 000 women worldwide every year, is considered the most arduous to treat subtype of breast cancer. With no targeted therapy, high rates of drug resistance and rapid metastasis, TNBC carries a poor prognosis. The MEK-ERK-MAPK signaling cascade is known to play a role in numerous cancers. Despite the lack of activating Ras/MAPK mutations in breast cancer, transcriptional signatures of this pathway are prevalent in TNBC. Our previous work showed that TNBC patients with tumors overexpressing ERK2 had a lower overall survival rate than did patients with low-ERK2-expressing tumors. MEK Inhibitors selumetinib (AZD6244) and pimasertib (AS703026) are active in preclinical models, but not as single agents in the clinic. Using a synthetic lethal siRNA screen, we identified myeloid cell leukemia-1 ( MCL1 ) as a potential contributor to selumetinib resistance. Mcl-1 is an anti-apoptotic protein that is highly amplified in numerous human cancers. It is associated with cell immortalization, transformation, and chemoresistance. Patients with TNBC tumors expressing high levels of Mcl-1 have lower overall survival and distant-metastasis-free survival rates. We hypothesized that Mcl-1 promotes MEK Inhibitor resistance in TNBC. Methods/Results: To model MEK Inhibitor resistance, we established selumetinib- and pimasertib-resistant clones of SUM-149 and MDA-MB-231 TNBC cells by continuous exposure to increasing concentrations of Inhibitors over a six month period. We confirmed the onset of MEK resistance by demonstrating that resistant cells, in comparison to the parental cells, exhibited no change in cell proliferation upon treatment with the MEK Inhibitors. Resistant cells also displayed more effective cell migration and mammosphere formation than parental cells, suggesting a higher fraction of tumor-initiating cells. We found Mcl-1 to be highly expressed in 83% (15 of 18) of TNBC cell lines but only 30% (3 of 10) of other breast cancer cell lines. Resistant cells had higher levels of Mcl-1 than did parental cells. To determine whether Mcl-1 is required for MEK sensitivity, we treated parental and resistant cells with either selumetinib or pimasertib together with S63845, a highly specific Mcl-1 Inhibitor. The Mcl-1 Inhibitor restored MEK sensitivity in both resistant cell lines. After treatment with the Mcl-1 Inhibitor, the resistant SUM-149 and MDA-MB-231 cells had similar cell proliferation rates to those of their parental counterparts. Similar studies were done using an siRNA against Mcl-1. Conclusion: Our data demonstrate that Mcl-1 may promote TNBC resistance to MEK Inhibitors and that Mcl-1 is a promising target for combination therapy. We will continue to explore the mechanisms of MEK Inhibitor resistance by screening for additional genes/pathways involved. Our long-term goal is to design rational combination approaches to counteract the emergence of resistance by using novel molecularly targeted therapeutics. Citation Format: Gagliardi M, Chauhan G, Pitner MK, Iles L, Qi Y, Pusztai L, Tripathy D, Bartholomeusz G, Bartholomeusz C. Overcoming MEK Inhibitor resistance in triple-negative breast cancer by targeting myeloid cell leukemia-1 ( MCL1 ), an anti-apoptotic protein [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-06.
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MEK Inhibitor selumetinib (AZD6244; ARRY-142886) prevents lung metastasis in a triple-negative breast cancer xenograft model
Molecular cancer therapeutics, 2015Co-Authors: Chandra Bartholomeusz, Paul D. Smith, Ali Dadbin, Hitomi Saso, Kimie Kondo, Jangsoon Lee, Xuemei Xie, Mary Kathryn Pitner, Kevin N. Dalby, Naoto T. UenoAbstract:Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with extracellular signal-regulated kinase 2 (ERK2)-overexpressing tumors were at higher risk of death than those with low-ERK2-expressing tumors (hazard ratio, 2.76; 95% confidence interval, 1.19-6.41). The MAPK pathway has been shown to be a marker of breast cancer metastasis, but has not been explored as a potential therapeutic target for preventing TNBC metastasis. Interestingly, when we treated TNBC cells with the allosteric MEK Inhibitor selumetinib, cell viability was not reduced in two-dimensional culture. However, in three-dimensional culture, selumetinib changed the mesenchymal phenotype of TNBC cells to an epithelial phenotype. Cells that undergo epithelial-mesenchymal transition (EMT) are thought to contribute to the metastatic process. EMT leads to generation of mesenchymal-like breast cancer cells with stem cell-like characteristics and a CD44(+)CD24(-/low) expression pattern. We tested the hypothesis that targeted inhibition of the MAPK pathway by selumetinib inhibits acquisition of the breast cancer stem cell phenotype and prevents lung metastasis of TNBC. TNBC cells treated with selumetinib showed inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P < 0.005), and decreases in the CD44(+)CD24(-/low) fraction, ALDH1 activity, and mammosphere-forming efficiency. Mice treated with selumetinib formed significantly fewer lung metastases than control mice injected with vehicle (P < 0.05). Our data demonstrate that MEK Inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis in certain cases in which tumors are MAPK dependent.
Gary K Schwartz - One of the best experts on this subject based on the ideXlab platform.
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Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells
Molecular cancer therapeutics, 2014Co-Authors: Grazia Ambrosini, Raya Khanin, Richard D. Carvajal, Gary K SchwartzAbstract:The majority of uveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11, with consequent activation of the MAPK pathway. Selective MEK Inhibitors, such as selumetinib, have shown clinical benefit in uveal melanoma. However, mechanisms of drug resistance limit their efficacy in some patients. Analysis of MEK Inhibitor–resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity. This effect was mediated by the RNA helicase DDX43, which was remarkably overexpressed in these cells. Depletion of DDX43 in MEK Inhibitor–resistant cells decreased RAS proteins and inhibited ERK and AKT pathways. On the contrary, ectopic expression of DDX43 in parental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition. Similar to DDX43 depletion, downregulation of KRAS, HRAS, and NRAS inhibited downstream pathways in the resistant cells, overcoming mutant GNAQ signaling. We also analyzed the expression of DDX43 in liver metastases of patients with uveal melanoma by RT-PCR, and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy. In conclusion, DDX43 induces RAS protein expression and signaling, mediating a novel mechanism of MEK Inhibitor resistance. The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this disease. Mol Cancer Ther; 13(8); 2073–80. ©2014 AACR .
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Abstract 5035: The MEK Inhibitor AZD6244 is active in GNAQ mutant ocular melanoma cells
Cellular and Molecular Biology, 2010Co-Authors: Grazia Ambrosini, Gary K SchwartzAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Uveal melanoma represents the most common intraocular malignancy in the United States. However, there are no effective treatments for this aggressive metastatic disease. While activating mutations in B-RAF are rare in ocular melanoma, oncogenic G protein alpha subunit q (GNAQ) mutations at codon 209 have been described in about 50% of uveal melanomas. Knock-down of GNAQ by siRNA inhibits p-ERK and the MEK Inhibitor U0126 has been shown to inhibit growth of a GNAQ mutant cell line (Van Raamsdonk CD et al, Nature 2009). AZD6244 (ARRY-142886) is a MEK Inhibitor now in clinical trials. Published phase I results have indicated clinical benefit in a patient with ocular melanoma (Adjei AA et al, J Clin Oncol. 2008). In view of this, we elected to test AZD6244 across a panel of ocular melanoma cell lines that differ in their GNAQ mutational status. Treatment with AZD4244 inhibited cell proliferation in a time- and dose-dependent manner, with IC50s in the 100-150nM range. This corresponded to the inhibition ERK phosphorylation and down-regulation of cyclin D1 in GNAQ mutant (both Q209L and P209L), but not in GNAQ wild-type cells. Over-expression of mutant GNAQ(Q209L) in wild type OCM290 cells, which are highly resistant to AZD6244, resulted in drug sensitization with inhibition of ERK phosphorylation. Depletion of GNAQ by siRNA in the GNAQ mutant cells resulted in inhibition of ERK phosphorylation and growth suppression. Interestingly, GNAQ depletion had no effect on ocular melanoma cells with wild type GNAQ or mutant B-RAF. We conclude that the GNAQ activating mutation in ocular melanoma can mediate sensitivity to AZD6244. This data provide a rationale for the clinical evaluation of AZD6244 in uveal melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5035.