BRAF-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape

Abstract

BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAF^V600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAF^V600E-mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAF^V600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.

FIG 1.

(A) Physiologic MAPK signaling. The MAPK cascade consists of a series of signaling steps that transduce extracellular signals to changes in gene expression to activate a program of growth, proliferation, and survival. Many steps of this pathway support amplification and specificity of the transmitted signals. The simplified schema shows that RTKs are first activated by extracellular growth factors and lead to recruitment of signaling proteins to the cell membrane and their activation, including RAS, which acts as a molecular switch that is at the on position when bound to GTP. RAS activates multiple downstream effectors, including the activation and dimerization of RAF to form RAF homo- and heterodimers. Activated RAF leads to MEK phosphorylation and activation, which leads to ERK phosphorylation and activation, and induction of a transcriptional program supporting cell growth and survival. (B) Characteristics of BRAF-mutant classes. (Left) Class I BRAF mutants, typified by BRAF^V600E, signal as constitutively activated monomers. They do not require RAS for activation. These mutants strongly activate ERK, so feedback suppresses upstream signaling; tumors with these mutants are characterized by RAS in the off GDP-bound state. (Center) Class II BRAF mutants, typified by BRAF^K601E, signal as constitutively activated mutant dimers. These also do not require RAS for activation, and feedback suppresses upstream signaling. There is likely a gradient of ERK activation and associated upstream feedback suppression across class II BRAF mutants. (Right) Class III BRAF mutants, typified by BRAF^D594G/N, amplify signaling in the pathway by binding more tightly to RAS and CRAF. They require upstream input to be oncogenic and increase ERK activation. GDP, guanosine 5' diphosphate; GTP, guanosine triphosphate; MAPK, mitogen-activated protein kinase; RTK, receptor tyrosine kinase.