Deja Vu: EGF receptors drive resistance to BRAF inhibitors

Abstract

The promise of personalized medicine is upon us, and in some cancers, targeted therapies are rapidly becoming the mainstay of treatment for selected patients based on their molecular profile. The protein kinase BRAF is a driver oncogene in both thyroid cancer and melanoma, but while drugs that target BRAF and its downstream signaling pathway are effective in melanoma, they are ineffective in thyroid cancer. In this issue of Cancer Discovery, Montero-Conde and colleagues investigate why thyroid cancer is resistant to BRAF inhibitors despite the presence of BRAF mutation.

Figure 1. Mechanisms of resistance to BRAF inhibitors

(A) Grey rectangle: mutant BRAF (BRAF^V600E) hyper-activates ERK signaling and promotes tumor cell proliferation and survival, but BRAF and MEK drugs inhibit the pathway and block tumor progression. Main figure: resistance to BRAF inhibitors is mediated by several mechanisms, including expression of a truncated forms of mutant BRAF, increased expression of mutant BRAF or wild-type CRAF, acquisition of mutations in RAS or MEK, expression of MAP3K8/COT, loss of PTEN expression, or activation of the receptor tyrosine kinases PDGFRβ, IGF-1R, EGFR and HER2/HER3, or increased activation of MET through the increased secretion of HGF by the stromal compartment. (B) EGF family receptors mediate resistance to BRAF inhibitors. In colorectal cells BRAF inhibits HER1 by inducing CDC25C, so BRAF inhibition by vemurafenib (Vem) releases the block to HER1 activation by reducing CDC25C expression. In thyroid cancer cells HER3 expression is inhibited by BRAF through the CtBP1/2 transcription repressors, so BRAF inhibition by vemurafenib (Vem) results in increased HER3 expression, and it alsoincreases NRG1 expression through unknown mechanisms. In melanoma, BRAF inhibition by vemurafenib (Vem) drives HER1 signaling by increasing EGF secretion, increasing HER1 expression and suppressing MIG6 activity through unknown mechanisms.

Figure 1. Mechanisms of resistance to BRAF inhibitors

(A) Grey rectangle: mutant BRAF (BRAF^V600E) hyper-activates ERK signaling and promotes tumor cell proliferation and survival, but BRAF and MEK drugs inhibit the pathway and block tumor progression. Main figure: resistance to BRAF inhibitors is mediated by several mechanisms, including expression of a truncated forms of mutant BRAF, increased expression of mutant BRAF or wild-type CRAF, acquisition of mutations in RAS or MEK, expression of MAP3K8/COT, loss of PTEN expression, or activation of the receptor tyrosine kinases PDGFRβ, IGF-1R, EGFR and HER2/HER3, or increased activation of MET through the increased secretion of HGF by the stromal compartment. (B) EGF family receptors mediate resistance to BRAF inhibitors. In colorectal cells BRAF inhibits HER1 by inducing CDC25C, so BRAF inhibition by vemurafenib (Vem) releases the block to HER1 activation by reducing CDC25C expression. In thyroid cancer cells HER3 expression is inhibited by BRAF through the CtBP1/2 transcription repressors, so BRAF inhibition by vemurafenib (Vem) results in increased HER3 expression, and it alsoincreases NRG1 expression through unknown mechanisms. In melanoma, BRAF inhibition by vemurafenib (Vem) drives HER1 signaling by increasing EGF secretion, increasing HER1 expression and suppressing MIG6 activity through unknown mechanisms.