Vemurafenib, a small molecule inhibitor of mutant BRAF proteins, has recently become the mainstay of therapy for the BRAF mutant metastatic melanomas1. However, the majority of the treated patients rapidly develop progressive disease due to acquired drug resistance. The main mechanisms of resistance reported include activation of specific Receptor Tyrosine Kinases (RTKs) 2.
We assessed a panel of 22 mutant BRAFmelanoma lines, and those intrinsically resistant to vemurafenib expressed higher levels of multiple receptor tyrosine kinases (RTKs) including EGFR, FGFR1 and cMET, but lower levels of other RTKs such as IGFR and cKIT. We have overexpressed these RTKs in four separate- drug-sensitive melanoma cell lines. In all cases, ligand activation of EGFR, FGFR1 and cMET were able to confer a proliferative advantage and resistance to vemurafenib, whereas ligand activation of IGFR and KIT were not able to do the same. The intrinsically resistant lines also harboured low expression of the negative feedback regulator SPROUTY2 proteins. SPROUTY2 is a direct target of ERK signalling and it negatively regulates the RAF-MEK-ERK signalling pathway, including activation and cycling of specific RTKs such as EGFR, FGFR1 and c-MET. Down-regulation of SPROUTY2 during BRAF inhibition has been reported to confer early adaptive resistance to BRAF inhibition3. Our data has also revealed that the RTKs can differentially modulate SPROUTY2. Enforced expression of SPROUTY2 was unable to sustain RTK-mediated compensatory ERK signaling, proliferation or resistance to vemurafenib. RTK-signalling also has implications in promotion of resistance and migration of melanomas4. Hence a thorough understanding of the mechanisms of signalling through different RTKs and their regulation, has clinical relevance in directing treatment strategies for overcoming RTK-mediated resistance during disease progression.