Counteracting resistance to chemo-radiotherapy and to targeted therapy in solid tumors

Control of mutant BRAF (V600E) metastatic melanomas by the selective BRAF inhibitor (BRAF-I), vemurafenib, is limited by the the lack of complete response due to intrinsic resistance and the often rapid development of acquired resistance . By utilizing melanoma cell lines with acquired BRAF-I resistance, we demonstrate for the first time an association between BRAF-I resistance and PDGFR? upregulation in vitro and in vivo. PDGFR? inhibition by PDGFR?-specific shRNA restores melanoma cells' sensitivity to BRAF-I in vitro. These effects are mediated by inhibition of ERK and AKT activation, which is associated with BRAF-I resistance. Combining vemurafenib with a PDGFR? inhibitor (sunitinib or imatinib) in vitro and in vivo demonstrate a significantly greater anti-proliferative and pro-apoptotic effect than either agent individually. These effects reflect the inhibition of ERK and AKT activation, which inhibits the proliferation and induces apoptosis. We corroborated this finding by demonstrating PDGFR? upregulation in melanomas harvested from patients who demonstrated disease progression following treatment with BRAF-I. Furthermore, analysis of matched biopsies of BRAF-I treated melanoma patients before treatment, after 1-2 weeks of treatment and at the time of disease progression demonstrated that PDGFR? upregulation correlated with less tumor regression (based on RECIST criteria) and a shorter time to disease progression. Our results demonstrate that PDGFR? inhibitors (sunitinib or imatinib) in combination with vemurafenib can overcome BRAF-I resistance mediated by PDGFR?. Although we could not associate baseline PDGFR? with clinical outcome, our data suggest that monitoring patients for early up regulation of PDGFR? may identify those for whom combination therapy would be most appropriate.