Molecular Pathways and Mechanisms of BRAF in Cancer Therapy

Abstract

With the identification of activating mutations in BRAF across a wide variety of malignancies, substantial effort was placed in designing safe and effective therapeutic strategies to target BRAF. These efforts have led to the development and regulatory approval of three BRAF inhibitors as well as five combinations of a BRAF inhibitor plus an additional agent(s) to manage cancer such as melanoma, non-small cell lung cancer, anaplastic thyroid cancer, and colorectal cancer. To date, each regimen is effective only in patients with tumors harboring BRAFV600 mutations and the duration of benefit is often short-lived. Further limitations preventing optimal management of BRAF-mutant malignancies are that treatments of non-V600 BRAF mutations have been less profound and combination therapy is likely necessary to overcome resistance mechanisms, but multi-drug regimens are often too toxic. With the emergence of a deeper understanding of how BRAF mutations signal through the RAS/MAPK pathway, newer RAF inhibitors are being developed that may be more effective and potentially safer and more rational combination therapies are being tested in the clinic. In this review, we identify the mechanics of RAF signaling through the RAS/MAPK pathway, present existing data on single-agent and combination RAF targeting efforts, describe emerging combinations, summarize the toxicity of the various agents in clinical testing, and speculate as to where the field may be headed.

Figure 1:. Frequency of BRAF alterations across cancers.

Graph showing portion of V600 BRAF and oncogenic non-V600 BRAF alterations across cancers. CRC: colorectal cancer. ECD: Erdheim Chester Disease. NSCLC: non-small cell lung cancer. PANC: pancreatic cancer.

Figure 2:. Combinatorial pharmacologic strategies tailored to BRAF alteration and RAS/MAPK signaling context.

Therapeutic strategies aimed at inhibiting the totality of RAS/MAPK signaling output would require a) a direct “pathway” inhibitor (e.g. MEK, ERK or CDK4/6 inhibitor), b) a BRAF alteration inhibitor (e.g. RAF monomer, RAF dimer, equipotent or Paradox Breaker inhibitor) and c) an “adaptive response” inhibitor (e.g. SHP2, SOS, RTK, or a RAF dimer inhibitor). A. Physiologic (“normal”) RAS/MAPK signaling. B. For tumors expressing Class I (BRAFV600E/K) and low RTK activity (e.g. a portion of melanomas), RAF monomer-selective inhibitors in combination with MEK inhibitors are effective. C. Acquired resistance to RAF monomer inhibitors is most commonly the result of RAF dimerization (expression of dimeric splice variant shown here, as an example), indicating tumor sensitivity to RAF dimer (or equipotent) inhibitors or Paradox Breakers in this context. D. For tumors expressing Class I (BRAFV600E/K) and high RTK activity (e.g. a portion of Colorectal Cancers), RAF monomer-selective inhibitors should be combined with “adaptive response” inhibitors (e.g. EGFR, or RAF dimer inhibitors), in addition to pathway inhibitors. E. Effective targeting of tumors expressing class II/III BRAF altered proteins that are either bound to RAS, or form RAS-independent dimers (F), would require an inhibitor targeting RAF (e.g. RAF dimer (or equipotent) inhibitor, or a Paradox Breaker), a pathway inhibitor (e.g. MEKi, ERKi) and an adaptive response inhibitor (e.g. SHP2i, SOSi, RTKi). Achieving both potent RAS/MAPK inhibition in the tumor and acceptable therapeutic index requires understanding and optimizing the biochemical properties of each inhibitor and their combination. Image by Christos Adamopoulos.

Figure 3:. Response to RAF inhibitors across cancers.

Graph showing response to RAF inhibitor monotherapy or RAF inhibitor combination (RAF and MEK inhibitors or, for colorectal cancer, RAF and EGFR inhibitors). Disease types without reported combination trial data are indicated in orange. Size of data points corresponds to number of trial patients used to estimate response: smallest points (1–50 patients), middle sized points (51–100 patients), large points (>200 patients). Graphed response rate for ECD corresponds to PET response. CRC: colorectal cancer. ECD: Erdheim Chester Disease. NSCLC: non-small cell lung cancer. PANC: pancreatic cancer. NA: not accessed.