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Neil L Spector - One of the best experts on this subject based on the ideXlab platform.
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Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in erbb2 overexpressing breast cancers
Cancer Research, 2007Co-Authors: Wenle Xia, Sarah S Bacus, Intisar Husain, Shermini Saini, Janice Spohn, Ron E Westlund, Steven H Stein, Leihua Liu, Karen Pry, Neil L SpectorAbstract:Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that Lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following Lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of Lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, Lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in Lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by Lapatinib in either cell line. In addition, Lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to Lapatinib monotherapy regardless of PTEN status. Thus, Lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer.
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Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in erbb2 overexpressing breast cancers
Cancer Research, 2007Co-Authors: Intisar Husain, Sarah S Bacus, Shermini Saini, Janice Spohn, Ron E Westlund, Steven H Stein, Neil L SpectorAbstract:Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that Lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following Lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of Lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, Lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in Lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by Lapatinib in either cell line. In addition, Lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to Lapatinib monotherapy regardless of PTEN status. Thus, Lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer. [Cancer Res 2007;67(3):1170–5]
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a model of acquired autoresistance to a potent erbb2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Sarah S Bacus, Priti S Hegde, Intisar Husain, Jay C Strum, Georgina Paulazzo, Ljuba Lyass, Patricia Trusk, Jason Hill, Jennifer L Harris, Neil L SpectorAbstract:The development of acquired resistance to ErbB2 tyrosine kinase inhibitors limits the clinical efficacy of this class of cancer therapeutics. Little is known about the mechanism(s) of acquired resistance to these agents. Here we establish a model of acquired resistance to N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2 (methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (Lapatinib), an inhibitor of ErbB2 and ErbB1 tyrosine kinases by chronically exposing Lapatinib-sensitive ErbB2-overexpressing breast cancer cells to Lapatinib, simulating the clinic where Lapatinib is administered on a daily chronic basis. Analysis of baseline gene expression in acquired Lapatinib-resistant and parental cells indicates estrogen receptor (ER) signaling involvement in the development of resistance. Using gene interference, we confirm that acquired resistance to Lapatinib is mediated by a switch in cell survival dependence and regulation of a key antiapoptotic mediator from ErbB2 alone to codependence upon ER and ErbB2 rather than loss of ErbB2 expression or insensitivity of ErbB2 signaling to Lapatinib. Increased ER signaling in response to Lapatinib is enhanced by the activation of factors facilitating the transcriptional activity of ER, notably FOXO3a and caveolin-1. Importantly, we confirm that Lapatinib induces ER signaling in tumor biopsies from patients with ErbB2-overexpressing breast cancers receiving Lapatinib therapy. These findings provided the rationale for preventing the development of acquired resistance by simultaneously inhibiting both ER and ErbB2 signaling pathways. Establishing clinically relevant models of acquired resistance to ErbB2 kinase inhibitors will enhance therapeutic strategies to improve clinical outcomes for patients with ErbB2-overexpressing breast cancers.
Kevin M Koch - One of the best experts on this subject based on the ideXlab platform.
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Effect of Lapatinib on oral digoxin absorption in patients.
Clinical pharmacology in drug development, 2015Co-Authors: Kevin M Koch, Leanne Cartee, Deborah A. Smith, Nikita Arya, Jeff Botbyl, Linda P. Briley, Jane Holshouser White, Jennifer Beyer, Mohammed M. Dar, Hyun Choel ChungAbstract:The potential for an interaction between Lapatinib and absorption of the P-glycoprotein (ABCB1) substrate digoxin at a therapeutic dose in breast cancer patients was characterized. Seventeen women with HER2-positive metastatic breast cancer received a single oral 0.5-mg dose of digoxin on days 1 and 9 and oral Lapatinib 1500 mg once daily on days 2 through 9. Digoxin pharmacokinetic parameters were determined on day 1 (digoxin administration alone) and on day 9 (coadministration of Lapatinib and digoxin), and parameters were compared to determine the effects of Lapatinib on digoxin absorption. Concomitant medications that could affect ABCB1 were accounted for. Lapatinib 1500 mg/day increased digoxin absorption approximately 80%, implicating Lapatinib inhibition of intestinal ABCB1-mediated efflux. In summary, coadministration of Lapatinib with narrow therapeutic index drugs that are substrates of ABCB1 should be undertaken with caution and dose adjustment should be considered.
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Effects of Esomeprazole on the Pharmacokinetics of Lapatinib in Breast Cancer Patients.
Clinical pharmacology in drug development, 2013Co-Authors: Kevin M Koch, Sung-bae Kim, Ander Urruticoechea Ribate, Joe Stephenson, Jeffrey Botbyl, Leanne Cartee, Jane Holshouser, Derry RidgwayAbstract:The aqueous solubility of Lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on Lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg Lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (Lapatinib alone) and Day 14 (Lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased Lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate.
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Effects of ketoconazole and carbamazepine on Lapatinib pharmacokinetics in healthy subjects.
British journal of clinical pharmacology, 2009Co-Authors: Deborah A. Smith, Kevin M Koch, Nikita Arya, Carolyn J. Bowen, Jill M Herendeen, Andrew P. BeelenAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Lapatinib is an orally administered tyrosine kinase inhibitor indicated for use in combination with capecitabine to treat advanced or metastatic breast cancers that overexpress ErbB2 in patients previously treated with anthracyclines, taxanes and trastuzumab. • In vitro studies have suggested that Lapatinib is metabolized primarily by CYP3A4, that it is a substrate of the efflux transporter ABCB1, and that it is a modest inhibitor of both CYP3A4 and ABCB1. • However, no data regarding the in vivo metabolism of Lapatinib have as of yet been reported. WHAT THIS STUDY ADDS • The in vivo pharmacokinetics of Lapatinib in healthy subjects was determined in the presence of a potent inhibitor (ketoconazole) or inducer (carbamazepine) of CYP3A4. • The results indicated that systemic exposure to Lapatinib was significantly altered by inhibition or induction of CYP3A4. • Thus, dose adjustments may be required when Lapatinib is administered orally concomitantly with drugs that potently alter CYP3A4 activity. AIMS To characterize the impact of potent CYP3A4 inhibition and induction on Lapatinib pharmacokinetics. METHODS Two studies were conducted in healthy subjects. One study examined the effect of ketoconazole 200 mg b.i.d. for 7 days on a single 100-mg dose of Lapatinib in 22 healthy subjects. The other study examined the effect of carbamazepine titrated up to 200 mg b.i.d. over 20 days on a single 250-mg dose of Lapatinib in 24 healthy subjects. RESULTS Ketoconazole altered Lapatinib AUC, Cmax and half-life, with geometric mean [95% confidence interval (CI)] increases of 3.57-fold (3.07, 4.15), 2.14-fold (1.74, 2.64) and 1.66-fold (1.50, 1.84), respectively, but had no effect on absorption rate. Carbamazepine altered Lapatinib AUC, Cmax and absorption rate, with geometric mean (95% CI) decreases of 72% (68, 77), 59% (49, 66) and 28% (4, 46), respectively, but had no effect on half-life. CONCLUSIONS Systemic exposure to Lapatinib was significantly altered by potent inhibition and induction of CYP3A4. Dose adjustments may be required when Lapatinib is administered with orally administered drugs that potently alter the activity of this enzyme.
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Phase I and Pharmacokinetic Study of Lapatinib and Docetaxel in Patients With Advanced Cancer
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2008Co-Authors: Patricia Lorusso, Kevin M Koch, Suzanne F Jones, Nikita Arya, Ronald A. Fleming, Jill Loftiss, Lini Pandite, Shirish M. Gadgeel, Barbara L. Weber, Howard A. BurrisAbstract:Purpose This phase I study assessed the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of Lapatinib and docetaxel in patients with advanced solid tumors. Patients and Methods Doses of Lapatinib (oral once daily, continuous) and docetaxel (intravenous, every 3 weeks) were escalated in cohorts of at least three patients based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. The protocol was amended to include pegfilgrastim because of dose-limiting toxicity (neutropenia), and a second dose-escalation phase was conducted to determine the OTR for the combination of docetaxel, Lapatinib, and pegfilgrastim. After the determination of the OTR, the pharmacokinetics of Lapatinib and docetaxel were determined to estimate the potential for an interaction between docetaxel and Lapatinib at the OTR dose level. Results Fifty-two patients with advanced solid tumors were enrolled. The OTR dose level for Lapatinib and docet...
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the role of efflux and uptake transporters in n 3 chloro 4 3 fluorobenzyl oxy phenyl 6 5 2 methylsulfonyl ethyl amino methyl 2 furyl 4 quinazolinamine gw572016 Lapatinib disposition and drug interactions
Drug Metabolism and Disposition, 2008Co-Authors: Joseph W. Polli, Stephen Castellino, Kevin M Koch, Joan E. Humphreys, Kelly A. Harmon, Michael J Omara, Katie Olson, Lisa A St Johnwilliams, Cosette J SerabjitsinghAbstract:Lapatinib [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine, GW572016, Tykerb] is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing HER2 (ErbB2). In this work we investigated the role of efflux and uptake transporters in Lapatinib disposition and drug interactions. In vitro studies evaluated whether Lapatinib is a substrate for efflux transporters or an inhibitor of efflux/uptake transporters. In vivo studies included whole-body autoradiography and an evaluation of the role of efflux transporters on the intestinal absorption and brain penetration of Lapatinib using chemical or genetic knockout animals. Lapatinib is a substrate for the efflux transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Furthermore, Lapatinib is an inhibitor (IC50 values 0.025–5 μM) of Pgp, BCRP, and organic anion transporting polypeptide 1B1 (a hepatic uptake transporter). In contrast, Lapatinib yielded little inhibition on renal transporters (organic anion transporters, organic cation transporters, and uric acid transporter). In vivo studies demonstrated that brain concentrations of Lapatinib were low and influenced by efflux transporters at the blood-brain barrier. In contrast, systemic exposure of Lapatinib after oral dosing was unchanged when efflux by Pgp and BCRP was absent from the gastrointestinal tract. These in vitro and in vivo preclinical investigations provide a mechanistic basis for elucidating clinical drug interactions.
Jill M. Kolesar - One of the best experts on this subject based on the ideXlab platform.
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Lapatinib: A small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor—2 tyrosine kinases used in the treatment of breast cancer
Clinical Therapeutics, 2009Co-Authors: Amye J. Tevaarwerk, Jill M. KolesarAbstract:Abstract Background: Lapatinib is an oral, small-molecule, reversible inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) tyrosine kinases. In March 2007, the US Food and Drug Administration approved Lapatinib for use in combination with capecitabine in the treatment of advanced breast cancer overexpressing HER2 (HER2+). Objectives: The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of Lapatinib, and to review studies of the approved and investigational uses of Lapatinib. Methods: English-language reports of clinical trials of Lapatinib in patients with cancer were identified through searches of PubMed/MEDLINE (1990–October 2009) and the American Society of Clinical Oncology abstracts database (2003–2008). Search terms included Lapatinib, Tykerb, HER2, EGFR, breast cancer, dual tyrosine kinase inhibitor , and GW572016 . Results: Lapatinib was well tolerated in a Phase II monotherapy trial in patients with advanced breast cancer; however, the response was minimal in HER2+ patients, and no HER2− patients achieved an objective tumor response. A Phase II trial of Lapatinib monotherapy in 39 HER2+ patients with breast cancer and brain metastases yielded 1 partial response, although 15.4% of patients had stable disease for ≥16 weeks. In a Phase III trial comparing Lapatinib plus capecitabine with capecitabine alone in HER2+ patients with advanced breast cancer that had progressed after trastuzumab therapy, the median time to progression was 8.4 months with combination therapy, compared with 4.4 months with capecitabine alone ( P Conclusions: Lapatinib monotherapy was well tolerated, although the response rate was low in patients with advanced breast cancer. Lapatinib combined with capecitabine was associated with significant improvements in the time to progression and response rate compared with capecitabine alone. The available evidence suggests that clinical efficacy in breast cancer is limited to HER2+ disease.
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Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer.
Clinical therapeutics, 2009Co-Authors: Amye J. Tevaarwerk, Jill M. KolesarAbstract:Lapatinib is an oral, small-molecule, reversible inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) tyrosine kinases. In March 2007, the US Food and Drug Administration approved Lapatinib for use in combination with capecitabine in the treatment of advanced breast cancer overexpressing HER2 (HER2+). The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of Lapatinib, and to review studies of the approved and investigational uses of Lapatinib. English-language reports of clinical trials of Lapatinib in patients with cancer were identified through searches of PubMed/MEDLINE (1990-October 2009) and the American Society of Clinical Oncology abstracts database (2003-2008). Search terms included Lapatinib, Tykerb, HER2, EGFR, breast cancer, dual tyrosine kinase inhibitor, and GW572016. Lapatinib was well tolerated in a Phase II monotherapy trial in patients with advanced breast cancer; however, the response was minimal in HER2+ patients, and no HER2- patients achieved an objective tumor response. A Phase II trial of Lapatinib monotherapy in 39 HER2+ patients with breast cancer and brain metastases yielded 1 partial response, although 15.4% of patients had stable disease for > or =16 weeks. In a Phase III trial comparing Lapatinib plus capecitabine with capecitabine alone in HER2+ patients with advanced breast cancer that had progressed after trastuzumab therapy, the median time to progression was 8.4 months with combination therapy, compared with 4.4 months with capecitabine alone (P < 0.001). There were no significant differences between combination therapy and capecitabine alone in terms of the overall response rate (22% and 14%, respectively) or overall survival. Lapatinib monotherapy was well tolerated, although the response rate was low in patients with advanced breast cancer. Lapatinib combined with capecitabine was associated with significant improvements in the time to progression and response rate compared with capecitabine alone. The available evidence suggests that clinical efficacy in breast cancer is limited to HER2+ disease. Copyright 2009 Excerpta Medica Inc. All rights reserved.
Kunwei Shen - One of the best experts on this subject based on the ideXlab platform.
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Effect of curcumin on Lapatinib sensitivity and Lapatinib resistance associated EMT and stem-like phenotype in HER2 positive breast cancer.
Journal of Clinical Oncology, 2015Co-Authors: Junjun Liu, Xiaosong Chen, Yan Mao, Kunwei ShenAbstract:e11594 Background: Lapatinib acquired resistance remains an important reason influencing Lapatinib clinical efficacy in HER2+ breast cancer. The epithelial-mesenchymal transition (EMT) and stem-like phenotype are key development programs often associated with cancer progression and drug resistance. Curcumin has potential therapeutic activities against breast cancer through multiple signaling pathways. We wished to determine the effect of curcumin on EMT and stem-like cells elicited by Lapatinib resistance and investigate curcumin as a potential therapeutic agent for HER2+ breast cancer. Methods: Two HER2+ breast cancer cell lines, SKBR3 and BT474 were continuously exposed to increasing concentrations of Lapatinib (0.25-2.6μmol/L) to establish two stable Lapatinib-resistant cell lines, SK-LR and BT-LR. Protein expression was determined by western-blot. Invasion ability was analyzed by transwell. Results: Both two Lapatinib-resistant cell lines, SK-LR and BT-LR had EMT and stem-like phenotype with higher in...
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Combined effects of Lapatinib and bortezomib in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and activity of bortezomib against Lapatinib-resistant breast cancer cells.
Cancer science, 2010Co-Authors: Xiuqing Niu, Jianmin Luo, Zhimin Shao, Kunwei ShenAbstract:Lapatinib and bortezomib are highly active against breast cancer cells. Breast cancer patients who initially respond to Lapatinib may eventually manifest acquired resistance to this treatment. Thus, the identification of novel agents that may prevent or delay the development of acquired resistance to Lapatinib is critical. In the current study, we show that the combination of Lapatinib and bortezomib results in a synergistic growth inhibition in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and that the combination enhances apoptosis of SK-BR-3 cells. Importantly, we found that the combination of Lapatinib plus bortezomib more effectively blocked activation of the HER2 pathway in SK-BR-3 cells, compared with monotherapy. In addition, we established a model of acquired resistance to Lapatinib by chronically challenging SK-BR-3 breast cancer cells with increasing concentrations of Lapatinib. Here, we showed that bortezomib notably induced apoptosis of Lapatinib-resistant SK-BR-3 pools and further inhibited HER2 signaling in the resistant cells. Taken together, the current data indicate a synergistic interaction between Lapatinib and bortezomib in HER2-overexpressing breast cancer cells and provide the rationale for the clinical evaluation of these two noncross-resistant targeted therapies. The combination of Lapatinib and bortezomib may be a potentially novel approach to prevent or delay the onset of acquired resistance to Lapatinib in HER2-overxpressing/estrogen receptor (ER)-negative breast cancers.
Eric Lam - One of the best experts on this subject based on the ideXlab platform.
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Lapatinib sensitivity in nasopharyngeal carcinoma is modulated by SIRT2-mediated FOXO3 deacetylation
BMC cancer, 2019Co-Authors: Sathid Aimjongjun, Zimam Mahmud, Yannasittha Jiramongkol, Glowi Alasiri, Shang Yao, Ernesto Yague, Tavan Janvilisri, Eric LamAbstract:Chemoresistance is an obstacle to the successful treatment of nasopharyngeal carcinoma (NPC). Lapatinib is a targeted tyrosine kinase inhibitor therapeutic drug also used to treat NPC, but high doses are often required to achieve a result. To investigate the mechanism for the development of Lapatinib resistance, we characterised a number of NPC cell lines to determine the role of FOXO3 and sirtuins in regulating NPC resistance. Sulforhodamine B (SRB) assays, Clonogenic assays, Protein extraction, quantification and western blotting, RT qPCR, Co-immunoprecipitation assay. To explore novel treatment strategies, we first characterized the Lapatinib-sensitivity of a panel of NPC cell lines by SRB and clonogenic cytotoxic assays and found that the metastatic NPC (C666–1 and 5-8F) cells are highly resistant whereas the poorly metastatic lines (6-10B, TW01 and HK-1) are sensitive to Lapatinib. Western blot analysis of the Lapatinib-sensitive 6-10B and resistant 5-8F NPC cells showed that the expression of phosphorylated/inactive FOXO3 (P-FOXO3;T32), its target FOXM1 and its regulator SIRT2 correlate negatively with Lapatinib response and sensitivity, suggesting that SIRT2 mediates FOXO3 deacetylation to promote Lapatinib resistance. In agreement, clonogenic cytotoxic assays using wild-type and foxo1/3/4−/− mouse embryonic fibroblasts (MEFs) showed that FOXO1/3/4-deletion significantly attenuates Lapatinib-induced cytotoxicity, confirming that FOXO proteins are essential for mediating Lapatinib response. SRB cell viability assays using chemical SIRT inhibitors (i.e. sirtinol, Ex527, AGK2 and AK1) revealed that all SIRT inhibitors can reduce NPC cell viability, but only the SIRT2-specific inhibitors AK1 and AGK2 further enhance the Lapatinib cytotoxicity. Consistently, clonogenic assays demonstrated that the SIRT2 inhibitors AK1 and AGK2 as well as SIRT2-knockdown increase Lapatinib cytotoxicity further in both the sensitive and resistant NPC cells. Co-immunoprecipitation studies showed that besides Lapatinib treatment, SIRT2-pharmaceutical inhibition and silencing also led to an increase in FOXO3 acetylation. Importantly, SIRT2 inhibition and depletion further enhanced Lapatinib-mediated FOXO3-acetylation in NPC cells. Collectively, our results suggest the involvement of SIRT2-mediated FOXO3 deacetylation in Lapatinib response and sensitivity, and that SIRT2 can specifically antagonise the cytotoxicity of Lapatinib through mediating FOXO3 deacetylation in both sensitive and resistant NPC cells. The present findings also propose that SIRT2 can be an important biomarker for metastatic and Lapatinib resistant NPC and that targeting the SIRT2-FOXO3 axis may provide novel strategies for treating NPC and for overcoming chemoresistance.
