American Association for Cancer Research

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Insight Into Melanoma Drug Resistance Pathways Identifies Potential New Treatment Option


November 21, 2013

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PHILADELPHIA — Although most of the melanomas that harbor BRAF mutations respond dramatically to treatment with BRAF inhibitors, nearly all develop resistance to the drugs in less than a year, and previous studies showed that melanomas alter a cell signaling pathway called the MAPK pathway to become resistant. New data suggest a second pathway called the PI3K-PTEN-AKT pathway may also be altered and thus, a combinatorial therapy approach to target the two core survival pathways when treatment is initiated may suppress drug resistance, according to two studies published in Cancer Discovery, a journal of the American Association for Cancer Research. Roger S. Lo, M.D., Ph.D.

“About 50 percent of melanomas are driven by mutations in the BRAF gene, and about 60-80 percent of these melanomas initially respond to BRAF inhibitors such as vemurafenib and dabrafenib, but most develop resistance within seven to eight months,” said Roger S. Lo, M.D., Ph.D., associate professor in the Department of Medicine at the Jonsson Comprehensive Cancer Center of the University of California, Los Angeles (UCLA) and a Stand Up To Cancer 2011 Innovative Research Grant recipient. “Our goal is to study comprehensively how this cancer escapes from BRAF inhibitors, so we can design new treatment approaches to overcome this resistance.

“There are several types of resistance, and one of these studies focused on early resistance, because most melanomas respond to BRAF inhibitors partially, leaving behind tumors subject to further evolutionary selection and development of late resistance,” said Lo. “We found that suppressing the BRAF-regulated MAPK signaling quickly led to an increase in PI3K-AKT pathway signaling [causing early resistance] in many but not all melanomas. In those that do not display this early adaptive response, certain tumor subclones with the ‘right’ genetic variants in the PI3K-PTEN-AKT pathway would then have selective growth advantage during BRAF inhibitor therapy and eventually contribute to acquired [late] resistance,” he explained.

Lo and colleagues studied melanoma tumors from patients collected before and early during treatment with BRAF inhibitors, and found that there was an increase in the amount of the activated form of a protein called AKT, early on after the start of treatment. They further confirmed these findings using melanoma cells cultured in the laboratory. This increase in activated AKT was associated with various inhibitors that block MAPK signaling at different points along the pathway, such as BRAF and MEK inhibitors.

In an accompanying paper, Lo and colleagues analyzed 100 tumor samples from 44 patients whose melanomas developed late resistance to therapy with a BRAF inhibitor, either vemurafenib or dabrafenib. Samples represented tumors collected before therapy and after the development of late resistance when melanomas reacquired the ability to grow during therapy.

By employing techniques including whole-exome sequencing and phylogenetic tree reconstruction, they found that 70 percent and 22 percent of the disease-progressive tumors had genetic alterations in the MAPK pathway and the PI3K-PTEN-AKT pathway, respectively. Both alterations were frequently found concurrently in the same tumor as well as in multiple tumors from the same patient.

“Our findings show that the degree of melanomas’ heterogeneity, when they evolve under the selective pressure and escape from the BRAF inhibitors, is rather extreme. As these tumors evolve, they become more fit and more aggressive than they were before treatment,” said Lo. “If melanomas turn on PI3K-AKT signaling to initially survive BRAF inhibitors and then to eventually regrow despite BRAF inhibitors, then this pathway needs to be dealt with pharmacologically. Targeting both core pathways is perhaps the best way to achieve a much more meaningful remission or control of this type of cancer.”

These studies were funded by a Stand Up To Cancer Innovative Research Grant, the National Cancer Institute, the Burroughs Wellcome Fund, the American Skin Association, the Melanoma Research Alliance, the Sidney Kimmel Foundation for Cancer Research, the Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, the Ian Copeland Melanoma Fund, the Harry J. Lloyd Charitable Trust, the National Center for Advancing Translational Sciences UCLA CTSI Grant, the Seaver Institute, the Wesley Coyle Memorial Fund, the Louis Belley and Richard Schnarr Fund, the Dr. Robert Vigen Memorial Fund, the Garcia-Corsini Family Fund, the Ruby Family Foundation, the Association of American Cancer Institutes, the National Health and Medical Research Council of Australia, the Translational Research Program of the Cancer Institute New South Wales, and the American Cancer Society Melanoma Research Professorship. Lo holds a patent application for the “Composition and Methods for Detection and Treatment of BRAF Inhibitor-resistant Melanomas.”