MAPK inhibitors provide critical treatment options for metastatic melanoma patients, but drug resistance emerges in more than 70 percent of cases, according to a study published by Nature Communications. Researchers found that targeting ABL kinases counters this resistance by reversing tumor-driven immune evasion.
The study deployed immune-proficient mouse models, single-cell RNA sequencing, flow cytometry, and patient clinical datasets to analyze therapeutic failure. ABL1 and ABL2 kinases promote resistance not only through intracellular signaling pathways, but also by triggering melanoma cells to secrete chemokines that suppress the surrounding immune microenvironment.
Targeting ABL1 and ABL2 reduced chemokine secretion by melanoma cells, prevented infiltration by immunosuppressive myeloid-derived suppressor cells, and promoted the accumulation of cytotoxic CD8+ T cells. Depleting myeloid-derived suppressor cells prevented resistance outright. In contrast, depleting CD8+ T cells or restoring chemokine expression prevented ABL inhibitors from blocking drug resistance.
Clinical data showed that CXCR2 receptor ligand expression and ABL1 and ABL2 activity both decreased in patients responding to MAPK inhibitors, but rose once resistance took hold.
Scientists from the University of Kentucky College of Medicine and the University of Zurich carried out the investigation, funded in part by National Cancer Institute grants R01 CA211137 and R01 CA258751. Pharmaceutical company Novartis provided nilotinib and dabrafenib for the research, while Memorial Sloan Kettering provided the SK-MEL-147 cell line.
