ABL1, ABL2 drive MAPK resistance and immune suppression in melanoma

New research shows that melanoma cells not only develop resistance to MAPK (Mitogen-Activated Protein Kinase) inhibitors commonly used to treat it, but also actively suppress the immune cells that would otherwise help eliminate melanoma.

The study, published in Nature Communications, identified two cell proteins, ABL1 and ABL2, as key drivers of both processes. These proteins help control cell functions such as growth, survival, and communication with other cells, and when they become overactive, they drive tumour growth. In melanoma, they help the cells keep growing by reactivating the growth signals despite treatment. Meanwhile, they can also trigger a signal that recruits immune-suppressing cells while keeping cancer-fighting T-cells at bay.

“These findings reveal that treatment resistance isn’t happening only inside the melanoma cell,” said lead author and University of Kentucky College of Medicine researcher Rakshamani Tripathi, PhD, in a press release. “ABL1 and ABL2 also help reshape the tumour’s immune environment, essentially creating another layer of protection that allows the cancer to survive therapy.”

Researchers at the University of Kentucky’s Markey Cancer Center in Lexington, Ky., are developing an approach to circumvent these two pathways of treatment resistance. Nilotinib is a medication approved by the U.S. Food and Drug Administration for chronic myeloid leukemia that blocks ABL proteins. Markey researchers tested nilotinib against multiple melanoma cell lines in preclinical models, with encouraging results: It shut down growth and survival signals and reduced the cancer’s ability to attract immune-suppressing cells, allowing T-cells to return.

In the release, the researchers say their findings confirm melanoma’s ABL proteins as a therapeutic target, opening up new possibilities for effective treatment.

“What makes this approach promising is the possibility of attacking resistance from two directions by blocking the cancer’s survival signals while allowing the immune system to reengage,” said Rina Plattner, PhD, professor in the University of Kentucky College of Medicine Department of Pharmacology and Nutritional Sciences. “Our results provide a strong rationale for continuing to study this strategy and translating it into clinical care.”