New perspectives for targeting RAF kinase in human cancer
Open accessAbstract
The discovery that a subset of human tumours is dependent on mutationally deregulated BRAF kinase intensified the development of RAF inhibitors to be used as potential therapeutics. The US Food and Drug Administration (FDA)-approved second-generation RAF inhibitors vemurafenib and dabrafenib have elicited remarkable responses and improved survival of patients with BRAF-V600E/K melanoma, but their effectiveness is limited by resistance. Beyond melanoma, current clinical RAF inhibitors show modest efficacy when used for colorectal and thyroid BRAF-V600E tumours or for tumours harbouring BRAF alterations other than the V600 mutation. Accumulated experimental and clinical evidence indicates that the complex biochemical mechanisms of RAF kinase signalling account both for the effectiveness of RAF inhibitors and for the various mechanisms of tumour resistance to them. Recently, a number of next-generation RAF inhibitors, with diverse structural and biochemical properties, have entered preclinical and clinical development. In this Review, we discuss the current understanding of RAF kinase regulation, mechanisms of inhibitor action and related clinical resistance to these drugs. The recent elucidation of critical structural and biochemical aspects of RAF inhibitor action, combined with the availability of a number of structurally diverse RAF inhibitors currently in preclinical and clinical development, will enable the design of more effective RAF inhibitors and RAF-inhibitor-based therapeutic strategies, tailored to different clinical contexts.
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BRAF inhibitors led to a monotherapy response rate of >50% in BRAFV600E melanoma and ~30% in BRAFV600E NSCLC, but only ~5% in BRAFV600E colorectal cancer, likely due to the variable robustness of adaptive feedback networks in each tumor type.
“For instance, BRAF inhibitors led to a monotherapy response rate of >50% in BRAFV600E melanoma and ~30% in BRAFV600E NSCLC, but only ~5% in BRAFV600E colorectal cancer, likely due to the variable robustness of adaptive feedback networks in each tumor type (45–49).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [48]
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- Authors
- Karoulia, Z., Gavathiotis, E., & Poulikakos, P. I.
- Affiliations
- Tisch Cancer Institute (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Poulikakos, Poulikos I.
- Venue
- Nature Reviews Cancer
- Published
- 2017-10-06
- Volume
- 17
- Issue
- 11
- Pages
- 676-691
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC6000833
- OpenAlex
- W2762842128
- Cited by
- 404
- References
- 125
- Citations by year
- 2026: 24 · 2025: 37 · 2024: 48 · 2023: 48 · 2022: 46 · 2021: 52 · 2020: 51 · 2019: 58 · 2018: 37 · 2017: 2
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Dermatology Foundation
- Melanoma Research Alliance
- Sidney Kimmel Foundation for Cancer Research
- Sidney Kimmel Foundation
- Pershing Square Sohn Cancer Research Alliance
- National Institutes of Health
- National Cancer Institute (R01CA178394, R01CA204314)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Raf kinase, BRAF mutation, RAF inhibitors, vemurafenib, dabrafenib, melanoma, BRAF V600E mutation, drug resistance, colorectal cancer, thyroid cancer, inhibitor design
- MeSH terms
- Humans, Neoplasms, Protein Kinase Inhibitors, raf Kinases
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