Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Apr;8(2):100788.
doi: 10.1016/j.esmoop.2023.100788. Epub 2023 Feb 24.

Precision oncology for BRAF-mutant cancers with BRAF and MEK inhibitors: from melanoma to tissue-agnostic therapy

M A Gouda  1 , V Subbiah  2
Affiliations
Review

Precision oncology for BRAF-mutant cancers with BRAF and MEK inhibitors: from melanoma to tissue-agnostic therapy

M A Gouda et al. ESMO Open. 2023 Apr.

Abstract

BRAF activation occurs as part of the mitogen-activated protein kinase (MAPK) cellular signaling pathway which leads to increased cellular proliferation and survival. Mutations in BRAF can result in unbridled activation of downstream kinases with subsequent uncontrolled cellular growth that formulate the basis for oncogenesis in multiple tumor types. Targeting BRAF by selective inhibitors has been one of the early successes in precision oncology. Agents have been explored either as monotherapy or in combination with MEK inhibition in BRAF V600-mutant pan-cancers and with EGFR inhibition in colorectal cancer. Spectrum of BRAF inhibition has evolved from being melanoma-specific to being a pan-cancer target. In this article, we review BRAF and MEK inhibitor drug development journey from tissue-specific melanoma, non-small-cell lung cancer, and anaplastic thyroid cancer to tissue-agnostic approvals.

Keywords: BRAF; MEK; cancer; precision oncology; targeted therapy.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Targeting BRAF pathway: figure shows the BRAF signaling pathway and cancers with the highest frequency of BRAF alterations according to AACR GENIE. Included are only cancers where BRAF was profiled in at least 100 samples. BRAFi, BRAF inhibitor; MEKi, MEK inhibitor.
Figure 2
Figure 2
Timeline of BRAF inhibitor drug development from melanoma to tissue-agnostic approval. ATC, anaplastic thyroid carcinoma; BTC, biliary tract cancer; CRC, colorectal cancer; ECD, Erdheim–Chester disease; FDA, Food and Drug Administration; HCL, hairy cell leukemia; NSCLC, non-small-cell lung cancer.
Figure 3
Figure 3
Response rates in different tumor types for BRAF inhibitors as monotherapy and in combination with MEK inhibitors in multiple tumors and EGFR inhibitors in colorectal cancer. Independent review data are used whenever reported in the most updated analysis. ATC, anaplastic thyroid carcinoma; BTC, biliary tract cancer; CRC, colorectal cancer; ECD, Erdheim–Chester disease; HCL, hairy cell leukemia; HGG, high-grade glioma; LGG, low-grade glioma; NSCLC, non-small-cell lung cancer.
See this image and copyright information in PMC

References

    1. Wellbrock C., Karasarides M., Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004;5:875–885. - PubMed
    1. Pearson G., Robinson F., Beers Gibson T., et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–183. - PubMed
    1. Subbiah V., Baik C., Kirkwood J.M. Clinical development of BRAF plus MEK inhibitor combinations. Trends Cancer. 2020;6:797–810. - PubMed
    1. Davies H., Bignell G.R., Cox C., et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954. - PubMed
    1. AACR Project GENIE Consortium AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov. 2017;7:818–831. - PMC - PubMed

Publication types

MeSH terms

Substances