Critical insights into how melanoma tumors resist BRAF inhibitors were gained from two back-to-back studies. Two key areas are the cell-signaling pathways BRAF-mutant melanoma cells use to learn how to become resistant to inhibitor drugs, and how the limited focus of BRAF inhibitors allows melanoma cells to evolve and develop drug resistance.
Approximately 40% of advanced melanoma tumors—the deadliest form of skin cancer, which can spread throughout the body—are driven to grow by the presence of BRAF mutations. New drugs called BRAF inhibitors have shown unprecedented responses as a treatment for these types of tumors, rapidly shrinking them. However, BRAF-mutated tumors frequently show early resistance to treatment and respond only partially to BRAF inhibitors, leaving behind cancer cells that lead to eventual tumor regrowth.
Led by Roger Lo, MD, PhD, of the University of California at Los Angeles and associate professor and director of the melanoma clinic in dermatology, these two studies utilized patient biopsy samples to give researchers powerful information that can be translated directly into the clinic, specifically to improve the use of BRAF inhibitor drugs in combination with other potential drugs for melanoma patients. The studies were published in Cancer Discovery (2013; doi:10.1158/2159-8290.CD-13-0642; doi:10.1158/2159-8290.CD-13-0279).
In the first study, Lo and colleagues discovered how tumor cells escaped the effects of BRAF inhibitors, based on the outgrowth of melanoma cells that had learned from different cell-signaling pathways how to become BRAF-inhibitor resistant. This work was based on the analysis of 100 biopsies from patients treated with BRAF inhibitors, and it highlights that BRAF inhibitor-resistant tumors use a variety of different signaling routes to learn resistance. Remarkably, a single patient could have more than one of these resistance routes.
“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 these melanoma patients,” Lo said.
The second study, also led by Lo, 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). Over time, these early adaptive resistance pathways are further fortified, allowing the tumor cells to break free of the BRAF inhibitor and resume growth. Therefore, early and late resistance processes are linked, and the endgames can be quite similar, although the means or mechanisms to these ends may be different. Discovering the common denominator or core melanoma escape pathways is an important conceptual advance when fighting BRAF inhibitor resistance.