Major finding: MEK inhibition suppresses HRAS-mutant skin tumors in BRAF inhibitor–treated mice.
Concept: Secondary tumors with RAS mutations arise due to paradoxical MAPK activation.
Impact: BRAF inhibitors do not initiate cancer but potentiate preexisting oncogenic RAS mutations.
Approximately 15% to 30% of melanoma patients treated with BRAF inhibitors such as vemurafenib develop cutaneous squamous-cell carcinomas and keratoacanthomas within the first few weeks of therapy, but the mechanisms underlying the rapid formation of these secondary malignancies remain incompletely characterized. Previous studies have indicated that BRAF inhibitors drive paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type tumor cell lines harboring RAS mutations. Furthermore, a recent analysis of squamous-cell carcinomas and keratoacanthomas in BRAF inhibitor–treated patients identified several mutations in RAS genes. Su and colleagues identified frequent RAS mutations in the vemurafenib–treated tumors they tested, with the most prevalent mutation being HRAS Q61L. The vast majority of the tumors arose in patients with chronically sun-damaged skin, suggesting that these mutations may have existed prior to treatment. To further characterize the interaction between BRAF inhibitors and mutant HRAS, the authors exposed cells harboring HRAS mutations to vemurafenib and observed that treatment induced anchorage-independent growth in soft agar that corresponded with increased extracellular signal-regulated kinase (ERK) phosphorylation and expression of MAPK pathway genes. Because these observations were consistent with a mechanism whereby paradoxical activation of the MAPK pathway by vemurafenib drives proliferation of HRAS-mutant cells, the authors tested the effects of BRAF inhibition in a mouse skin carcinogenesis model. The vemurafenib analogue PLX4720 dramatically accelerated tumor growth in mice treated with carcinogens and tumor promoters but did not induce tumors in mice treated with carcinogens alone. Thus, PLX4720 accelerated tumor growth in susceptible individuals but is not a tumor promoter. Further, the MAP–ERK kinase (MEK) inhibitor PD184352 almost completely blocked the growth of the tumors, providing preclinical evidence that MEK inhibitors may prevent secondary tumor development driven by BRAF-drug mediated paradoxical activation of the MAPK pathway in cells with oncogenic RAS mutations.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at www.AACR.org/CDnews.
