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Paradoxical oncogenesis—the long-term effects of BRAF inhibition in melanoma

Nature Reviews Clinical Oncology volume 10, pages 390–399 (2013)Cite this article

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Abstract

The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps. In most cases, paradoxical MAPK activation—resulting from the BRAF-inhibitor-mediated homodimerization and heterodimerization of nonmutant RAF isoforms—seems to underlie the development of these secondary tumours. Although evidence supports that therapy with the simultaneous administration of BRAF and MEK inhibitors abrogates the onset of treatment-induced SCCs, whether combination treatment will limit the emergence of all BRAF-inhibitor-driven pathologies is unclear. In this Review, we describe the clinical and mechanistic manifestations of secondary cancers that have thus far been observed to arise as a consequence of BRAF inhibition. We discuss the concept of pre-existing populations of partly transformed cells with malignant potential that might be present in various organ systems, and the rationale for novel therapeutic strategies for the management of BRAF-inhibitor-induced neoplasia.

Key Points

  • BRAF inhibitors are commonly used in patients with BRAF-mutant melanoma and their use is expanding to other patient populations

  • Paradoxical activation of the MAPK pathway can occur in cells wild-type for BRAF through the BRAF-inhibitor-mediated formation of RAF dimers

  • Secondary skin changes, including hyperkeratosis, keratoacanthomas and squamous-cell carcinomas, can occur in patients treated with BRAF inhibitors

  • Secondary melanomas, gastric and colonic polyps and recurrences of pre-existing malignancies have also been reported in patients receiving BRAF inhibitors

  • Strategies to manage or limit the development of treatment-induced cancers include combination therapy with inhibitors of BRAF and MEK, and use of retinoids, topical 5-fluorouracil and cyclooxygenase-2 inhibitors

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Figure 1: RAF activation of the MAPK/ERK pathway.
Figure 2: Paradoxical activation of the MAPK/ERK pathway in tumours treated with RAF inhibitors.
Figure 3: Secondary cutaneous skin changes in patients receiving vemurafenib treatment.
Figure 4: MAPK signalling cooperates with loss of APC to promote adenoma development.

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Acknowledgements

K. S. M. Smalley is supported by NIH/National Cancer Institute grants (R01 CA161107-02 and U54 CA143970-03).

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Authors and Affiliations

  1. Department of Cutaneous Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, 33612, FL, USA

    Geoffrey T. Gibney & Vernon K. Sondak

  2. Department of Molecular Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, 33612, FL, USA

    Inna V. Fedorenko & Keiran S. M. Smalley

  3. Department of Pathology and Cell Biology, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, MDC 11, Tampa, 33612, FL, USA

    Jane L. Messina

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G. T. Gibney acts as a consultant or advisory board member for following companies: Genentech and Roche. All other authors declare no competing interests.

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Gibney, G., Messina, J., Fedorenko, I. et al. Paradoxical oncogenesis—the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol 10, 390–399 (2013). https://doi.org/10.1038/nrclinonc.2013.83

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