Unexpected MEK1 Mutations Not Cause of Potent Melanoma Drug Resistance

A genetic mutation in MEK1 does not prevent response to BRAF inhibitors in patients undergoing treatment for BRAF-mutated melanomas, contrary to current thought that the gene mutations might have been a cause of resistance.

This groundbreaking research was published online ahead of print in Cancer Discovery, a journal of the American Association for Cancer Research, and was presented here during a Stand Up To Cancer Press Event on Sunday, April 1, 2012, at 1:00 p.m. CT in Room 10 A/B/C of the Hyatt Conference Center, adjacent to McCormick Place.

BRAF mutations are found in more than 50 percent of melanomas. BRAF inhibitors can induce an antitumor response in about 60 percent of patients. Thus, a subset of tumors is drug resistant at the outset, and those patients who first responded can go on to develop resistance to the drugs.

“Another gene, known as MEK1, is rarely mutated in cancers, but in this study, we found to our surprise that mutated MEK1 was frequently associated with BRAF mutations,” said Roger S. Lo, M.D., Ph.D., assistant professor of medicine/dermatology at University of California, Los Angeles Jonsson Comprehensive Cancer Center in Los Angeles, Calif.

To explore the association between MEK1 and BRAF, Lo and colleagues analyzed tumor samples from 31 patients with melanoma treated with a BRAF inhibitor. Of these patients, 16 percent carried both BRAF and MEK1 mutations in tumors before drug treatment.

“Based on the current state of knowledge, the presence of both mutated MEK1 and mutated BRAF is thought to be a biomarker for BRAF inhibitor resistance in melanomas,” Lo said. “However, we were surprised again when we found that patients with double BRAF/MEK1-mutated melanomas can respond to BRAF inhibitors as well as patients with single BRAF-mutated melanomas.”

Specifically, three of five patients with double BRAF/MEK1-mutated melanomas had a tumor response to the BRAF inhibitors. Lo and colleagues further verified these conclusions using melanoma cell lines grown in the laboratory.

“These findings tell oncologists that these two groups of patients — those patients with BRAF-mutated melanomas and those with BRAF and MEK1-mutated melanomas — can be expected to respond similarly well to BRAF inhibitors or the combination of BRAF inhibitors plus MEK inhibitors,” Lo said.

Despite the fact that MEK1 is not a cause of BRAF inhibitor resistance, Lo and colleagues will continue to explore why BRAF and MEK mutations coexist in the same tumor to find novel ways to weaken tumors with both mutations. In addition, other possible causes for ongoing BRAF inhibitor resistance still need to be uncovered.

“We are pushing forward to uncover biomarkers of BRAF inhibitor sensitivity or resistance and hope to use them as a guide to formulate therapeutic strategies,” Lo said.

The research was funded by Stand Up To Cancer and exemplifies Stand Up To Cancer’s unique research model, according to Lo.

“It places strong emphasis on the study of human cancer tissues, on knowledge generation that will help patients with cancer today and on the power of collaboration that can accelerate both aforementioned points,” he said.

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About the AACR
Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR’s membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.

Source: American Association for Cancer Research (AACR)