Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma

Abstract

Almost 50% of metastatic melanoma patients harbor a BRAF(V600) mutation and the introduction of BRAF inhibitors has improved their treatment options. BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. However, most patients develop mechanisms of acquired resistance and about 15% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. Moreover, early adaptive responses limit the initial efficacy of BRAF inhibition, leading mostly to incomplete responses that may favor the selection of a sub-population of resistant clones and the acquisition of alterations that cause tumor regrowth and progressive disease. The purpose of this paper is to review the mechanisms of resistance to therapy with BRAF inhibitors and to discuss the strategies to overcome them based on pre-clinical and clinical evidences.

Figure 1

Under physiological conditions, ERK signaling is regulated by extracellular signals binding to receptor tyrosine kinases (RTKs). Activated RTKs promote RAS-mediated dimerization of RAF; wild-type RAF, as hetero- or homodimers, phosphorylate and activate MEK1/2, which in turn phosphorylate and activate ERK1/2. Activated ERK promote cell cycle progression and proliferation and negatively regulates upstream signaling components (negative feedback). RTKs also regulate the PI3K-AKT-mTOR pathway. The two pathways interact at multiple points: most importantly, RAS directly binds and activates PI3K.

Figure 2

In BRAF-mutated cells, BRAFV600E is constitutively active as a monomer, leading to high ERK signaling and elevated ERK-dependent transcriptional output, including negative-feedback components. As a result, RAS expression is low and does not promote RAF dimerization, and PI3K/AKT signaling is substantially attenuated.