A Feedback Loop Modulates Melanoma Sensitivity to BRAF Inhibitors

ERK activity is regulated via negative feedback mechanisms that attenuate ligand-stimulated RAS signaling and downstream RAF dimerization. Elevated ERK activity is characteristic of BRAF^V600E melanomas and can be inhibited by RAF inhibitors such as vemurafenib that selectively target mutant BRAF monomers; however, acquired resistance to these drugs often develops due to alterations that result in RAF dimerization. Lito and colleagues hypothesized that ERK-dependent feedback suppression of RAS activity prevents RAF dimerization in BRAF-mutant melanomas and that relief of this feedback contributes to RAF-inhibitor resistance. Indeed, BRAF^V600E melanomas exhibited low levels of RAS activity at baseline that were induced following treatment with RAF or MEK inhibitors. This was associated with decreased expression of Sprouty proteins, as well as activation of CRAF and increased ERK phosphorylation, suggesting that RAF inhibitors promote loss of this feedback loop and subsequent reactivation of RAS signaling. The rebound in ERK activity following treatment with RAF inhibitors was dependent on CRAF expression and RAS-mediated formation of BRAF–CRAF heterodimers that retained sensitivity to MEK inhibition but were resistant to vemurafenib retreatment. In addition, relief of ERK-driven feedback potentiated ligand-stimulated RAS signaling and enhanced the response of BRAF^V600E cells to exogenous growth factors, which diminished the inhibitory effects of vemurafenib. In contrast, treatment with an EGF receptor/HER kinase inhibitor reduced ERK reactivation and BRAF–CRAF dimerization and restored MEK suppression by vemurafenib, suggesting that combined inhibition of receptor tyrosine kinases and BRAF is necessary for maximal antitumor activity. Furthermore, concurrent inhibition of MEK and RAF signaling prevented the rebound of ERK signaling and augmented the suppression of tumor growth in melanoma xenograft models. These findings identify a mechanism of tumor adaptation to ERK inhibition and suggest combinatorial therapeutic strategies that may improve the treatment of melanoma.

Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 2012;22:668–82.

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