Lauren Gatta

A collaboration between researchers at Yale, the University of Massachusetts Medical School and the Vanderbilt Medical Center has determined a new cause of melanoma treatment resistance.

More than 50 percent of melanomas contain mutations in the BRAF gene, making BRAF the primary target of melanoma treatment. Thus, BRAF kinase inhibitors, or BRAFi, which block protein action, comprise the main approach to melanoma treatment. Published in the journal PNAS on Feb. 19, the study found that one form of resistance to these inhibitors is caused by the loss of a protein called Block of Proliferation 1.

“Recurrence and resistance are the two most important problems in melanoma therapy, which are what this research is trying to address. Acquired resistance is a very difficult problem. Drawing from these findings, we would ideally try to directly engage with patients who develop melanoma resistance,” said Romi Gupta, first author and pathology researcher at the Yale School of Medicine.

Drugs such as vemurafenib and dabrafenib act on these oncogenic BRAF gene mutations by inhibiting BRAF kinases. However, melanoma treatment efficacy is limited by acquired resistance to these BRAFi treatments. Thus, these drugs only serve as temporary solutions for most patients, as they are effective only for a short period of time.

Although several reasons for acquired BRAFi resistance have been identified, more than 40 percent of cases of acquired resistance to BRAFi remain mysterious. The study’s identification of the loss of Block of Proliferation 1, or BOP1, function as the cause of BRAFi resistance brings new insights to melanoma treatment and suggests an additional biological target to enhance treatment efficacy.

Gupta noted that expanding the scale of this study to include more patients may allow a broader application of these insights in a clinical setting.

“Researchers are now trying to conduct large-scale screens that employ many genes and epigenetic factors in an unbiased fashion,” she added.

In the study, a large-scale RNA screen was conducted to pinpoint epigenetic regulators — which alter gene activity and expression but are not part of the DNA sequence — involved in melanoma resistance. According to Gupta, a library of 363 known epigenetic regulators served as potential candidates for melanoma resistance, and the one seen most often in  melanoma resistance was BOP1.

In addition, Gupta said that most previous studies on BRAFi resistance have focused on genetic factors. Only recently have researchers discovered that epigenetic factors are also extensively involved in cancer and function in tandem with genetic factors.

Gupta stressed the importance of epigenetic research in cancer, adding that targeted therapy for these resistance factors will be far more effective in combatting resistance than existing approaches.

“In the coming years, many more epigenetic factors will be identified. Targeting these [epigenetic factors] would have a very beneficial effect on treating cancer patients,” she said.

Gupta added that with a more advanced portfolio of genetic and epigenetic biomarkers to screen for potential BRAFi resistance development in patients, more personalized therapies with enhanced prevention of melanoma recurrence can be developed in the future.

According to Gupta, the finding that BOP1 loss causes resistance makes BOP1 an excellent biomarker for prediagnosing resistance. This causal link serves as an important breakthrough for preventative care and personalized approaches to melanoma treatment, she said.

By diagnosing BOP1 levels in early stages of treatment, oncologists may now be able to more accurately predict whether a patient would undergo resistance to BRAFi in the future and alter the treatment plan accordingly, the study noted. This predictive power of BOP1 as a biomarker for BRAFi resistance could serve as indicators for changes in dosage or more thorough controls for recurrence in patients with BOP1.

Cases of melanoma have been steadily rising in the past 30 years, becoming one of the leading causes of mortality among skin cancers, according to the Skin Cancer Foundation. According to the American Cancer Society, an estimated 96,480 new cases of melanoma will be diagnosed in 2019.

Viola Lee | kyounga.lee@yale.edu