Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations

Abstract

The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants. As next generation sequencing becomes increasingly used in clinical practice, oncologists are frequently identifying non-V600 BRAF mutations in their patient's tumors, but are uncertain of viable therapeutic options that could be employed for optimal treatment. From recent studies, a new classification system is emerging for BRAF mutations based on biochemical and signaling mechanisms associated with these mutants. Class I BRAF mutations affect amino acid V600 and signal as RAS-independent active monomers, class II mutations function as RAS-independent activated dimers, and class III mutations are kinase impaired but increase signaling through the MAPK pathway due to enhanced RAS binding and subsequent CRAF activation. These distinct classes of BRAF mutations predict response to targeted therapies and have important implications for future drug development. Herein, we discuss pre-clinical and clinical findings that may lead to improved treatments for all classes of BRAF mutant cancers.

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

“…Mutations generating class 2 (eg K601E, G469A and F595L) or class 3 (eg G469E) mutants have also been described in iCCA . Class 2 and class 3 mutants are oncogenic, but insensitive to currently available BRAF inhibitors . Regardless of the structural bases underpinning their signalling activity, all classes of BRAF mutants drive cell transformation through activation of the MEK/ERK module, which creates the opportunity of interfering with their activity through MEK1/2 blockade .…”

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

“…The Class I, BRAF Val 600 , variants are uncommon in RASopathies (Li et al, ), but non‐Val 600 Class II and Class III BRAF variants are observed in CFC. Class II BRAF variants function as RAS‐independent constitutively active dimers, while Class III BRAF variants increase MAPK signaling due to an increased ability to be activated by RAS (Dankner, Rose, Rajkumar, Siegel, & Watson, ). The RAF family member RAF1 is rarely mutated in cancer, but germline pathogenic variants in RAF1 are found in individuals with NS (Pandit et al, ).…”

BRAF Mutation Class and Clinical Outcomes—Letter

“…As such, they are identifying more patients whose tumors express non-V600 BRAF mutations. Until recently, the prognostic and therapeutic relevance of these mutations was poorly understood (2). Dagogo-Jack and colleagues have published the largest and most comprehensive clinical dataset to date, derived from patients with BRAF-mutant NSCLC, including both non-V600 (class 2 and 3) and V600 (class 1) mutations.…”

“…There is now a growing body of evidence demonstrating that class 2/3 BRAF mutations are associated with an aggressive clinical course in NSCLC and melanoma (1)(2)(3). These are actionable mutations and effective targeted therapies are thus warranted.…”