Study Finds Drug-Resistant Melanoma Treatments May Be Enhanced
November 22, 2013

Drug-Resistant Melanoma Treatment May Be Enhanced: Study

April Flowers for - Your Universe Online

More than 8,000 Americans are killed each year by melanoma -- the deadliest form of skin cancer. The presence of mutations in a gene known as the BRAF gene drives approximately 40 percent of advanced melanoma tumors.

New medications, called BRAF inhibitors, have shown an ability to rapidly shrink melanoma tumors, however BRAF-mutated tumors often resist early treatment and only partially respond to BRAF inhibitors, which leaves behind cancer cells that can eventually grow into new tumors.

Researchers from UCLA's Jonsson Comprehensive Cancer Center led an international team of scientists in conducting two studies that provide critical insights into two important ways that tumors resist BRAF inhibitors. The team discovered the key cell-signaling pathways used by BRAF-mutant melanoma to become drug resistant. They also discovered that the limited focus of the BRAF inhibitors allow melanoma cells to evolve and become drug-resistant. The results of these studies were published online in the journal Cancer Discovery and will be published later in the print edition.

Dr. Roger Lo, a member of the UCLA Jonsson Comprehensive Cancer Center and associate professor and director of the melanoma clinic in dermatology led the studies, which utilized patients' biopsy samples to give researchers powerful information that can be translated directly into the clinic. The researchers hope that their findings will help oncologists make better use of BRAF inhibitor drugs in combination with other drugs for melanoma patients.

Nearly all BRAF mutation melanomas develop resistance to BRAF inhibitors within one year. Prior studies have shown that melanomas alter a cell signaling pathway called the MARK pathway to create this resistance. The new study suggests a second pathway, PI3K-PTEN-AKT, may also be altered. A combinatorial therapy approach to target both pathways at once when treatment is initiated may suppress this drug resistance.

"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 Dr. Lo. "Our goal is to study comprehensively how this cancer escapes from BRAF inhibitors, so we can design new treatment approaches to overcome this resistance.

"It is very exciting to see work funded under a Stand Up To Cancer Innovative Research Grant (IRG) yield these important results," stated Sherry Lansing, co-founder & member of the SU2C Council of Founders and Advisors. "We created the IRG program to enable some of the best and brightest young researchers across disciplines to think out of the box and attempt to make major breakthroughs in their field with bold research projects."

The SU2C IRG program is one of two initial funding models created by SU2C to focus on groundbreaking translational research aimed at getting new therapies to patients quickly. IRG grants support work that incorporates new ideas and new approaches to solve critical problems in cancer research. Dr. Lo's grant was one of the initial 13 IRG grants awarded in December 2009. Thirteen additional IRG grants were awarded in April 2011. To date, SU2C has funded $19.42 million for IRG research.

"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, who is also a Allan H. (Bud) and Sue Selig Stand Up To Cancer Melanoma Innovative Research Grant Recipient, and his team discovered how tumor cells escaped the effects of BRAF inhibitors by tracking the outgrowth of melanoma cells in the first study. These cells had learned from different cell-signaling pathways how to become BRAF inhibitor-resistant. The researchers analyzed 100 biopsies from patients who had been treated with BRAF inhibitors. The data revealed that BRAF inhibitor–resistant tumors use a variety of different signaling routes to learn resistance and that people can have more than one resistance route. These phenomena have rarely been studied in clinical trials at the molecular level, which Lo said provides a much more robust view of the scale and scope of the problem.

By understanding the mechanisms of tumor resistance, doctors could identify the optimal combination of inhibitor drugs to block multiple resistance routes, which eventually could shrink tumors for a much longer period, or eradicate them completely.

"By helping us understand the core resistance pathways and tumor heterogeneity, fitness and mutational patterns that emerge under drug selection, this study lays a foundation for clinical trials to investigate the mechanisms of tumor progression in BRAF-mutant melanoma patients," Lo said.

Lo also led the second study, which found that as soon as melanomas face BRAF inhibitors they are able to quickly turn on drug resistance pathways—a process called early adaptive resistance. These early adaptive resistance pathways are further fortified over time, allowing tumor cells to break free of the BRAF inhibitor and resume growth. This links early and late resistance processes, which can lead to recurrence of cancer and death, although the means or mechanisms may be different. When fighting BRAF inhibitor resistance, the discovery of the core melanoma escape pathways is an important conceptual advance because treatments can then be designed to block these pathways all at once when treatment is initiated.

"We now have a landscape view of how melanoma first adapts and then finds ways to overcome what is initially a very effective treatment," said Dr. Antoni Ribas, a Jonsson Cancer Center member, professor of medicine and co-investigator on both studies. "We have already incorporated this knowledge into testing new combination treatments that we hope will get us back ahead of melanoma and not allow it to escape the initial treatment effectiveness and return."