Melanoma is one of the most difficult cancers to treat due to its resistance to targeted drug therapies. But a new study from the University of Markey Cancer Center shows that the cancer is playing offence as well as defence: In addition to forming resistance against the MAPK inhibitors that are commonly used to treat it, the cancer also actively suppresses the immune cells that would otherwise help eliminate it.
The study, published in Nature Communications, 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 tumour growth when they become overactive. In melanomas, they help the cells keep growing despite treatment by reactivating the growth signals. 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 UK College of Medicine researcher Rakshamani Tripathi, Ph.D. “ABL1 and ABL2 also help reshape the tumour’s immune environment, essentially creating another layer of protection that allows the cancer to survive therapy.”
But scientists are working on a new play: Nilotinib is a drug that is Food and Drug Administration-approved for chronic myeloid leukaemia, and it works by blocking ABL proteins. 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.
These 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 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.”
Source: University of Kentucky
