Vemurafenib, a small molecule inhibitor to mutant B-RafV600E protein, has recently become the mainstay of therapy for the BRAF mutant metastatic melanomas1, and also a landmark target-therapy owing to its clinical efficacy. However, the majority of the treated patients develop progressive disease due to acquired drug resistance. The main mechanisms of resistance reported include activation of various Receptor Tyrosine Kinases (RTKs)2.
Constitutive expression and ligand activation of EGFR, FGFR1 and MET in A375 cells were able to confer resistance, whereas IGF1R and c-KIT were not. The main difference in signalling between the two groups of RTKs was their ability to sustain activation of downstream signalling to ERK to maintain proliferation when mutant BRAF was inhibited. Our data has also revealed that the RTKs differentially modulate Sprouty2 (SPRY2), a negative feedback regulator of RTK and MAPK signalling. Enforced expression of SPRY2 was found able to reverse RTK-driven resistance to vemurafenib. Interestingly, receptor levels and activation could be altered following vemurafenib treatment, which varied depending on the specific RTK.
Our study suggests that various RTKs act differently in terms of their ability to maintain proliferation in the context of BRAF inhibition. Signalling through RTKs has implications in terms of cell growth, migration, metastasis and therapy resistance. Hence a thorough understanding of the specific roles of individual RTKs in melanoma progression will help monitor and direct combination treatments able to prevent or overcome disease progression.