Study Shows How Melanoma Resists Drugs and Immune Defenses

A new study conducted at the University of Kentucky (UK) Markey Cancer Center shows melanoma forms resistance against the MAPK inhibitors that are commonly used to treat it, while at the same time actively suppressing the immune cells that would otherwise help eliminate it.

In the study, researchers identified two cell proteins known as ABL1 and ABL2 as key drivers of both processes. These proteins help control cell functions such as growth, survival and communication with other cells, leading to tumor growth when they become overactive. In melanoma, they help the cells keep growing despite treatment by reactivating the growth signals. They can also trigger a signal that recruits immune-suppressing cells while resisting cancer-fighting T cells. These findings confirm melanoma’s ABL proteins as a therapeutic target, opening up new possibilities for effective treatment.

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

Knowing this, the researchers believe a drug, nilotinib, approved by the U.S. Food and Drug Administration to treat chronic myeloid leukemia, which works by blocking ABL proteins, can also be used to treat melanoma. Markey researchers have used nilotinib against multiple melanoma cell lines in preclinical testing models with encouraging results: It shut down the proteins’ growth and survival signals and reduced the cancer’s ability to attract immune-suppressing cells, which allowed T cells to return.

“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 UK 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.”