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The role of CRAF in cancer progression: from molecular mechanisms to precision therapies

Nature Reviews Cancer volume 24, pages 105–122 (2024)Cite this article

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Abstract

The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF and CRAF, drives tumour progression and drug resistance in many types of cancer. Although BRAF is the most studied RAF protein, partially owing to its high mutation incidence in melanoma, the role of CRAF in tumourigenesis and drug resistance is becoming increasingly clinically relevant. Here, we summarize the main known regulatory mechanisms and gene alterations that contribute to CRAF activity, highlighting the different oncogenic roles of CRAF, and categorize RAF1 (CRAF) mutations according to the effect on kinase activity. Additionally, we emphasize the effect that CRAF alterations may have on drug resistance and how precision therapies could effectively target CRAF-dependent tumours. Here, we discuss preclinical and clinical findings that may lead to improved treatments for all types of oncogenic RAF1 alterations in cancer.

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Fig. 1: Canonical RAF activation through mitogen-activated protein kinase signalling and potential therapeutic strategies.
Fig. 2: CRAF mutations and activation cycle.
Fig. 3: Characterizing the genomic landscape of tumours with RAF1 alterations.
Fig. 4: Potential therapeutic strategies according to kinase activity of RAF1 mutants and presence of co-occurring mitogen-activated protein kinase mutations.

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Data availability

The data that support the findings of this study are available at cBioportal and https://genie.cbioportal.org/.

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Acknowledgements

M.R. and I.S.-B. are recipients of Canadian Institutes of Health Research (CIHR) postdoctoral fellowships, J.M. is the recipient of an Elizabeth Steffen Memorial Fellowship and M.D. is the recipient of a Vanier Canada Graduate Scholarship. A.A.N.R. acknowledges support from a Fonds de Recherche du Québec – Santé (FRQS) Clinical Research Scholar Award. Funding for this research was provided by a Canadian Cancer Society Challenge Grant (#707457), a TransMedTech Institute and Apogee Canada Research Excellence Fund and the Louise Couture (Chartier) Memorial Fund to A.A.N.R.

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Author notes

  1. These authors contributed equally: Melody Riaud, Jennifer Maxwell, Isabel Soria-Bretones.

Authors and Affiliations

  1. Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada

    Melody Riaud, Isabel Soria-Bretones, Meredith Li & April A. N. Rose

  2. Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada

    Melody Riaud, Jennifer Maxwell, Isabel Soria-Bretones, Matthew Dankner & April A. N. Rose

  3. Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

    Jennifer Maxwell & April A. N. Rose

  4. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    Isabel Soria-Bretones

  5. Faculty of Medicine, McGill University, Montreal, Quebec, Canada

    Matthew Dankner

  6. Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada

    Matthew Dankner

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Contributions

M.R., J.M., I.S.-B., M.D. and A.A.N.R. wrote the article. M.R., J.M. and I.S.-B. contributed equally to all aspects of the article. All authors researched data for the article. M.R., J.M., I.S.-B., M.D. and A.A.N.R. contributed substantially to discussion of the content. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to April A. N. Rose.

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Competing interests

I.S.-B. is an employee of Repare Therapeutics. A.A.N.R. reports research grants from the Canadian Institutes of Health Research (CIHR), the Canadian Cancer Society (CCS), Canada Foundation for Innovation (CFI) the Conquer Cancer Foundation of ASCO and Fonds de Recherche du Québec — Santé during the conduct of the study; personal fees from Advanced Accelerator Applications/Novartis and EMD Serono during the conduct of this study. A.A.N.R. reports institutional research funding for clinical research from: Bayer, Merck, Pfizer, AstraZeneca, and Seagen — not related to the submitted work. M.R., J.M., M.D. and M.L. have no competing interests.

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Supplementary information

Glossary

American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange version 14

(AACR GENIE v14). A multiphase, multiyear, international data-sharing project that aims to catalyse precision cancer medicine.

BRAF V600

The V600 mutation describes an amino acid substitution of the valine at position 600 in BRAF; the two most common mutations substitute a glutamic acid (E) or a lysine (K) amino acid resulting in a constitutively activated kinase.

Cardiofaciocutaneous disease

A syndrome in which patients have multiple congenital anomalies or intellectual disabilities; failure to thrive; psychomotor delay; a characteristic face; congenital heart defects; and abnormalities of the skin, eyes, gastrointestinal tract and central nervous system.

Histiocytic neoplasms

Hematologic disorders characterized by the accumulation of myeloid–dendritic cell-derived neoplastic cells with an accompanying inflammatory infiltrate; they account for less than 1% of cancers of the soft tissue and lymph nodes.

Oncogenic hotspot mutations

Recurrently mutated DNA positions in cancer, which confer tumourigenic properties to the affected gene.

Pheochromocytoma

A type of neuroendocrine tumour that originates from hormone-producing chromaffin cells within the adrenal glands.

Phosphomimetic substitution

Amino acid substitutions, commonly at serine, tyrosine and threonine, by introducing an amino acid with a phosphate group that mimics the effect of a phosphorylated protein, thereby activating (or deactivating) the protein.

Pilocytic astrocytomas

A family of slow-growing tumours that arise from glial cells that are mostly benign and thus are the most treatable type of the glioma with a cure rate of over 90%.

Pleomorphic xanthoastrocytoma

A very rare type of astrocytoma, which arises in the brain or spinal cord.

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Riaud, M., Maxwell, J., Soria-Bretones, I. et al. The role of CRAF in cancer progression: from molecular mechanisms to precision therapies. Nat Rev Cancer 24, 105–122 (2024). https://doi.org/10.1038/s41568-023-00650-x

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