BioProject

Selective RAF inhibitors including vemurafenib (PLX4032) have demonstrated clinical efficacy in mutant BRAF driven metastatic melanoma. More...

Selective RAF inhibitors including vemurafenib (PLX4032) have demonstrated clinical efficacy in mutant BRAF driven metastatic melanoma. The clinical effectiveness of RAF inhibitors depends on near complete abolition of the MAPK pathway output in tumors harboring BRAF mutations. However these compounds paradoxically activate the MAPK pathway in cells bearing oncogenic RAS or elevated upstream receptor signaling. This paradox can promote cellular proliferation and can manifest clinically with progression of secondary malignancies such as cutaneous squamous cell carcinomas (cuSCC). We have identified next generation RAF inhibitors (“paradox breakers”, e.g. PLX7904) that inhibit mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In murine cuSCC B9 cells that express the same HRAS mutation prevalent in squamous tumors from patients treated with RAF inhibitors, the first-generation RAF PLX4032 stimulated in vitro and in vivo growth; by contrast the paradox breaker PLX7904 had no effect. Here we compared the gene expression changes in B9 cells treated overnight with PLX4032 and PLX7904. Overall design: B9 cells were plated in 1 µM vemurafenib, 1 µM PLX7904 or 0.2% DMSO vehicle control and incubated for 17 hours. Cell lysates were harvested for RNA extraction and hybridization on Affymetrix Less...