New Studies Provide Insight Into Melanoma Drug Resistance Pathways and Strategy for Obtaining Durable Responses
Approximately 50% of metastatic melanomas harbor the BRAF mutation, and although most of these melanomas respond dramatically to treatment with BRAF inhibitors, such as vemurafenib (Zelboraf) and dabrafenib (Tafinlar), nearly all develop resistance to the drugs within 7 to 8 months. While previous studies have shown that melanomas change the MAPK cell-signaling pathway to become resistant, two new studies have found that a second pathway called PI3K-PTEN-AKT may also become altered, suggesting that an upfront combination drug approach that targets both pathways may be necessary to suppress drug resistance and achieve more durable responses. The studies are published in Cancer Discovery.
The studies were conducted by Roger S. Lo, MD, PhD, Associate Professor in the Department of Medicine at the Jonsson Comprehensive Cancer Center of the University of California, Los Angeles, and colleagues. In the first study, the researchers analyzed melanoma tumor specimens collected before and during early treatment—within the first month—with BRAF inhibitors and found that there was an increase in the amount of phosphorylated AKT. The findings were confirmed using melanoma cells cultured in the laboratory. The increase in the activated AKT was linked with various inhibitors, such as BRAF and MEK, that block MAPK signaling at different points along the pathway.
“We looked at different time points in treatment, and the reason that’s important is because the responses are not black and white,” said Dr. Lo. “The majority of patients don’t respond completely. After a while when the rest of the tumor stays in the body for a long time some of them will start to regrow, and that regrowth is what ultimately affects the progression-free survival.”
Study Methods
In the second study, Dr. Lo and colleagues analyzed 100 tumor samples from 44 patients whose melanomas developed late resistance to either vemurafenib or dabrafenib. The tumor samples were collected before therapy and after the development of late resistance when the melanomas reacquired the ability to grow during therapy. Using whole-exome sequencing and phylogenetic tree reconstruction, the researchers found that 70% and 22% of the disease-progressive tumors had genetic alterations in the MAPK pathway and the PI3K-PTEN-AKT pathway, respectively. In addition, both alterations were found concurrently in the same tumor or in multiple tumors from the same patient.
“What happens early and later are both very important,” said Dr. Lo. “The tumor needs to get used to the drug and adapts to it, but that part is not really genetic selection. Genetic selection takes a long time. So the first part of our study looked at the nongenetic process and the second part studied the genetic process. What we found is that there is a common denominator. The nongenetic tools that the cancer uses activates AKT. The genetic tools later on that allow the cancer to regrow again also activates AKT, so this is telling us that, either early or late, the cancer finds a way to turn on this pathway.”
Achieving More Durable Responses
Since BRAF-mutant melanomas acquire BRAF inhibitor resistance via upregulation of both MAPK and PI3K-AKT pathways, targeting both pathways in the upfront setting may be the best way to achieve a more durable remission in these melanomas, according to Dr. Lo.
Dr. Lo holds a patent application for the “Composition and Methods for Detection and Treatment of BRAF Inhibitor-Resistant Melanomas.”
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 Canter of Regenerative Medicine & Stem Cell Research, the Ian Copeland Melanoma Fund, the Harry J. Lloyd Charitable Trust, the National Center for advancing Translations 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.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
