Abstract 4478: EGFR tyrosine kinase inhibitors overcome resistance to chemotherapy in malignant pleural mesothelioma

Abstract

Abstract Background: Malignant pleural mesothelioma (MPM) is a cancer of the pleura mainly caused by exposure to asbestos fibers. Current treatments are unsatisfactory due to intrinsic chemoresistance of the tumor. We hypothesized that chemoresistance was due to epigenetic errors and evaluated the ability of HDAC inhibitors to improve treatment efficacy. We previously showed that valproic acid (VPA) improves the first line regimen of MPM both in vitro and in vivo (Vandermeers et al, 2009, Clinical Cancer Research 15: 2818). A clinical trial also demonstrated that VPA in combination with doxorubicin increases the response rate of second line patients (Scherpereel et al, 2011, European Respiratory Journal 37:129). Methods: Transcriptomic profiling was performed by microarray analyses (Agilent). Gene expression was validated by quantitative RT-qPCR. Modulation of TGFα expression was performed by shRNA interference and transfection of a cDNA vector. Onset of apoptosis was assessed with the Annexin V assay. Results: To evaluate the mechanisms associated with the response to chemotherapy, we compared two types of MPM cell lines (M14K and H28) characterized by a difference in sensitivity to doxorubicin+VPA. Microarray analyses and bioinformatic modeling of gene expression profiles revealed the most relevant candidate genes associated with sensitivity or resistance to this regimen. Among these, TGFα expression was associated with resistance to doxorubicin + VPA in a series of MPM cell lines. Silencing of TGFα by RNA interference in H28 cells correlated with a significant increase in apoptosis. On the other hand, overexpression of TGFα desensitized M14K cells to doxorubicin+VPA -induced apoptosis. Since TGFα interacts with the EGF receptor, we evaluated pharmacological inhibition using EGFR tyrosine kinase inhibitors (erlotinib and gefitinib) and the dual HDAC/EGFR inhibitor CUDC-101. As predicted, these TKI inhibitors improved efficacy of doxorubicin+VPA. Conclusions: Our data demonstrate that TGFα is involved in resistance of MPM to chemotherapy and that TKI inhibitors overcome resistance to second line regimen. Citation Format: Bernard Staumont, Chrisostome Costa, Fabian Vandermeers, Sathya Neelature Sriramareddy, Céline Mascaux, Arnaud Scherpereel, Bernard Duysinx, Renaud Louis, Philippe Delvenne, Pascale Hubert, Luc Willems. EGFR tyrosine kinase inhibitors overcome resistance to chemotherapy in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4478.