Targeting Oncogenic BRAF: Past, Present, and Future

Abstract

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a "precision medicine" paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

Keywords: BRAF; drug resistance; oncogene; precision medicine; targeted therapy.

Figure 1

Pan-cancer BRAF alterations from The Cancer Genome Atlas (TCGA). TCGA-generated pan-cancer alteration frequency of BRAF was extracted from cBioportal (https://www.cbioportal.org). Data are represented as a stacked histogram plot. Colors represent different types of alterations as indicated in the legend.

Figure 2

BRAF mutation spectrum in cancer. TCGA pan-cancer studies from cBioportal (https://www.cbioportal.org) were used for BRAF mutation lollipop plot. This plot summarizes 32 studies from TCGA that constitute 10,953 patients/10,967 samples. Somatic BRAF mutation frequency is 7.0% in these samples. The diagram shows the backbone of BRAF protein containing 766 amino acids (aa) with three main domains: (1) Raf-like RAS-binding domain (RBD, that spans 156–227 amino acids green), (2) phorbol esters/diacylglcerol-binding domain (C1 domain, 235–280aa, red), and (3) protein tyrosine kinase domain (Pkinase_Tyr, 458–712 aa, blue). The circles with different colors represent types of mutations: dark green, missense mutations; black, truncating mutations (including nonsense, nonstop, frameshift deletion, frameshift insertion, splice site mutations); dark red, in-frame deletion, in-frame insertion; pink, other mutations. Y-axis shows the frequency of particular BRAF mutations.

Figure 3

BRAF-mediated signaling in normal and cancer cells. In normal cells, external growth stimuli activate receptor tyrosine kinase (RTK) and RAS, which relays growth signals to the mitogen-activated protein kinase (MAPK) pathway kinase cascade. In BRAF-driven cancers, mutant BRAF (BRAF *) can either act RAS independently as a monomer (Class 1) and as a dimer (Class 2) or act RAS dependently (Class 3) to hyperactivate cellular growth. Class 1 and Class 2 tumors respond to BRAF inhibitor-targeted therapy. However, various intrinsic or adaptive resistance mechanisms attenuate response to targeted BRAF inactivation. For example, preexisting NF1 loss, CDK4 mutations, and increased COT and YAP expression may specify intrinsic resistance. Therapy-induced HGF secretion and PI3K-AKT pathway activation are examples of some of the adaptive resistance mechanisms. On the other hand, EGFR-amplified population gives rise to acquired resistance to BRAF inhibitors.

Figure 4

BRAF alterations concurrent with other genetic aberrations in non-small cell lung cancer (NSCLC). Targeted tumor exome sequencing using 403 cancer gene panel was performed by Foundation medicine. In all, 236 samples with BRAF alterations, such as structural variation (SV), copy number variation (CV), and rearrangement (RE), were stratified from 30,000 non-small cell lung cancer samples. Oncoprint of BRAF-mutant tumor shows coexistence of other genetic alterations with BRAF gene alteration. The different frequency of gene alterations is indicated on the left bar plot.