Abstract Background. Malignant mesothelioma (MM) is a cancer of the pleura caused mainly by the inhalation of asbestos fibers. The impact of chemotherapy on the outcome of patients with MM is still unclear. We hypothesized that unresponsiveness to chemotherapy is due to inadequate gene expression in tumor cells. We have previously shown that inhibitors of histones deacetylases (such as valproate, VPA) significantly increases the efficacy of compounds used in chemotherapy (Vandermeers et al, 2010, Clinical Cancer Research 15: 2818). A recent clinical trial on relapsing MM patients has shown that VPA in combination with doxorubicin improves response rates and quality of life (Scherpereel et al, 2011, European Respiratory Journal 37:129). Results. To study the mechanisms associated with the response to chemotherapy, we compared two types of cell lines (M14K and H28) characterized by a difference in sensitivity to doxorubicin+VPA. Using Agilent microarrays and RT-qPCR, we observed that the basal expression level of TGFα was higher in "resistant" H28 compared to "sensitive" M14K cells. To evaluate the functional relevance of TGFα, we modulated its expression either by RNA interference or by transfection of a cDNA vector. A decrease of TGFα expression correlated with induction of apoptosis. Inversely, an inhibition of apoptosis occurred when TGFα was over-expressed. As TGFα is the ligand of EGFR, we tested the effect of gefitinib and erlotinib in combination with VPA+doxorubicin. Both EGFR inhibitors increased apoptosis induced by VPA+doxorubicin in H28 chemoresistant cells. Finally, the VPA+doxorubicin+erlotinib regimen prevented tumor growth in two mouse models (ZL34 in SCID and AB12 in Balb/c). Conclusions. Our data demonstrates that TGFα is involved in the chemoresistance to VPA+doxorubicin, a second-line regimen for MM. Although inefficient alone, tyrosine kinase inhibitors synergize to induce apoptosis in chemoresistant cells and prevent tumor growth in mouse models. Citation Format: Sathya Neelature Sriramareddy, Fabian Vandermeers, Chrisostome Costa, Céline Mascaux, Arnaud Scherpereel, Philippe Delvenne, Pascale Hubert, Luc L. Willems. The role of TGF-alpha in the resistance to mesothelioma chemotherapy. [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 984. doi:10.1158/1538-7445.AM2013-984