Major finding: RAS mutations are common in secondary tumors of RAF inhibitor–treated patients.
Concept: RAF inhibition may upregulate MAPK signaling in latent RAS-mutant keratinocytes.
Impact: Combined RAF and MEK inhibition may prevent transformation of RAS-primed cells.
Selective RAF inhibition has been an effective therapeutic strategy for treatment of BRAF-mutant melanomas, but secondary skin tumors such as keratoacanthomas (KA) and cutaneous squamous cell carcinomas (cSCC) rapidly develop in approximately 25% of patients. Understanding why RAF inhibitors inhibit cancerous growth of one cell type while promoting oncogenic transformation in another is essential, as RAF inhibitors are poised to become more widely used. To address this question, Oberholzer and colleagues performed high-throughput genotyping of selected oncogenes and tumor suppressors in a large panel of archival cSCC and KA tumor specimens from patients who had received RAF inhibitor therapy, immunosuppressive therapy, or neither treatment. Strikingly, HRAS mutations were found in 4 of 19 (21%) of cSCCs and KAs from patients treated with vemurafenib or sorafenib, compared with 6 of 218 (3%) of the other tumors. Recent preclinical studies have demonstrated that RAF inhibitors can promote tumor growth by inducing MAP kinase signaling in cells with wild-type BRAF or CRAF and mutant RAS. The authors therefore propose that keratinocytes that have acquired RAS mutations (perhaps due in part to toxic cellular effects of UV radiation) are primed for transformation upon exposure to RAF inhibitors. Although a massive parallel sequencing–based approach will be needed to identify the other genomic alterations driving cSCC and KA formation in response to RAF inhibitors, these findings suggest that coinhibition of RAS downstream effectors (e.g., MAP/ERK kinsase) may be effective in preventing secondary cancer formation in a subset of melanoma patients.
Oberholzer PA, Kee D, Dziunycz P, Sucker A, Kamsukom N, Jones R, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol. 2011 Nov 7. [Epub ahead of print].
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