BRAF — A tumour-agnostic drug target with lineage-specific dependencies Review
| Authors: | Hanrahan, A. J.; Chen, Z.; Rosen, N.; Solit, D. B. |
| Review Title: | BRAF — A tumour-agnostic drug target with lineage-specific dependencies |
| Abstract: | In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAFV600E-mutant solid tumours, except for BRAFV600E-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAFV600E-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies. © Springer Nature Limited 2024. |
| Keywords: | adult; child; overall survival; somatic mutation; genetics; missense mutation; mutation; constipation; fatigue; neutropenia; review; sorafenib; placebo; diarrhea; monotherapy; nonhuman; solid tumor; glioma; antineoplastic agent; endometrium cancer; neoplasm; neoplasms; colorectal cancer; gastrointestinal stromal tumor; ipilimumab; melanoma; multiple cycle treatment; ovary cancer; anemia; protein kinase inhibitor; thrombocytopenia; antineoplastic combined chemotherapy protocols; cetuximab; cancer resistance; panitumumab; drug dose escalation; fever; pruritus; sarcoma; protein kinase inhibitors; acne; gene fusion; dimerization; thyroid cancer; negative feedback; oncogene k ras; astrocytoma; thyroid papillary carcinoma; everolimus; b raf kinase; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; lapatinib; biliary tract cancer; proto-oncogene proteins b-raf; braf protein, human; imidazoles; imidazole derivative; small intestine cancer; hairy cell leukemia; gastrointestinal cancer; non small cell lung cancer; metastatic melanoma; langerhans cell histiocytosis; tumor microenvironment; molecularly targeted therapy; metastatic colorectal cancer; female genital tract cancer; differentiated thyroid cancer; hypertransaminasemia; anaplastic thyroid carcinoma; navitoclax; germline mutation; vemurafenib; akt signaling; dabrafenib; trametinib; mapk signaling; nivolumab; oximes; humans; human; binimetinib; erdheim chester disease; ribociclib; encorafenib; cobimetinib; atezolizumab; defactinib; oxime; central nervous system cancer; ulixertinib; spartalizumab; triplet chemotherapy; doublet chemotherapy; tislelizumab; cobicistat; avutometinib; naporafenib; batoprotafib; belvarafenib; eras 254; exarafenib; lifirafenib; mirdametinib; n [5 (3 dimethylaminobenzamido) 2 methylphenyl] 4 hydroxybenzamide; plixorafenib; rineterkib; tovorafenib |
| Journal Title: | Nature Reviews Clinical Oncology |
| Volume: | 21 |
| Issue: | 3 |
| ISSN: | 1759-4774 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-03-01 |
| Start Page: | 224 |
| End Page: | 247 |
| Language: | English |
| DOI: | 10.1038/s41571-023-00852-0 |
| PUBMED: | 38278874 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is David B. Solit -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work