Melanoma: BRAF Inhibition May Switch Cancer Cells To Become More Metastatic

Keiran Smalley, PhD. Scientific Director, The Comprehensive Melanoma Research Center Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, Interview with:
Keiran Smalley, PhD.

Scientific Director, The Comprehensive Melanoma Research Center
Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, FL


Medical Research: What is the background for this study? What are the main findings?

Dr. Smalley: Although many patients with BRAF mutant melanoma respond very well to BRAF inhibitors and the BRAF/MEK inhibitor combination, resistance is commonplace and the majority of those treated ultimately fail therapy. Most studies to date have focused upon the genetic changes that are associated with acquired BRAF and BRAF/MEK inhibitor resistance. We decided to take a different approach and to use proteomics to comprehensively map all of the signaling changes associated with resistance. Our study showed that melanoma cells with resistance to BRAF and BRAF/MEK inhibition were highly invasive and aggressive. This aggressive phenotype was driven through a cell surface receptor called EphA2, and this became upregulated in both melanoma cell cultures and in patient tumors following BRAF inhibitor treatment. As this suggested that the resistant cells would be more metastatic, we then performed animal experiments and analyzed tumors from melanoma patients receiving BRAF inhibitor. These studies showed an increase in EphA2 expression in the metastatic tumors that was lacking in the primary tumors. When we looked at cohorts of melanoma patients who received either a BRAF inhibitor or an older chemotherapy drug, we found that more of the BRAF inhibitor treated patients seemed to develop disease at new sites. Together this suggested that BRAF inhibition may switch the cancer cells to being more metastatic.

Medical Research: What should clinicians and patients take away from your report?

Dr. Smalley: Although this may appear rather alarming, it is still worth remembering that BRAF mutant melanoma patients do better on BRAF inhibitors than on chemotherapy – their responses are better and are far more durable. The BRAF/MEK inhibitor combination is still a major success in the melanoma field and brings incredible benefit to patients. Our study adds to a growing body of work from other cancers showing that kinase inhibitors can sometimes alter the phenotype of the tumor and in some cases this may lead to more aggressive disease. One interesting observation that came out of this research was that this aggressive behavior was reversible. When the drugs were removed, the tumor reverted back to its initial state and stopped being invasive. This suggests that an alternate dose schedule of these drugs could be developed, where intermittent drug exposure could be used to limit tumor growth but not provide this strong selection for increased metastatic dissemination. There are already clinical trials being planned to address this issue.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Smalley: My overall recommendation is to further explore intermittent dosing schedules of BRAF and MEK inhibitors. It may be possible to still have the same therapeutic benefit while reducing the drug selection pressure that leads to the adoption of this aggressive phenotype.


Ligand independent EphA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype

Kim H. T. Paraiso, Meghna Das Thakur, Bin Fang, John M. Koomen, Inna V. Fedorenko, Jobin K. John, Hensin Tsao, Keith T. Flaherty, Vernon K. Sondak, Jane L. Messina, Elena B. Pasquale, Alejandro Villagra, Uma N. Rao, John M. Kirkwood, Friedegund Meier, Sarah Sloot, Geoffrey T. Gibney, Darrin Stuart, Hussein Tawbi, and Keiran S. M. Smalley

Cancer Discovery CD-14-0293; Published OnlineFirst December 26, 2014; doi:10.1158/2159-8290.CD-14-0293

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Last Updated on January 14, 2015 by Marie Benz MD FAAD