GPNMB overexpression- a marker of resistance to CDK4/6 inhibitors

Resistance to cyclin-dependent kinase 4/6 inhibitors remains a major clinical challenge in treating estrogen receptor-positive breast cancer, with no reliable predictive biomarkers currently available for patient selection. To investigate resistance mechanisms, we generated drug-tolerant persisters (DTPs) to abemaciclib and palbociclib in a panel of estrogen receptor-positive breast cancer cell lines. Functional analyses revealed that DTPs showed resistance to CDK4/6 inhibition, maintained G1 arrest, and exhibited increased senescence phenotype. To identify clinically relevant markers of resistance, we compared transcriptomic profiles from DTPs with publicly available gene-expression data from the phase III PEARL trial. Glycoprotein non-metastatic B (GPNMB) emerged as one of the most strongly upregulated transcripts in DTPs, and also was amongst the genes associated with resistance in the PEARL dataset. We further verified that GPNMB overexpression (GPNMB-OE) in sensitive cells conferred resistance to CDK4/6 inhibition, and enhanced migratory capacity. Overexpression of GPNMB drove substantially faster tumor progression and eliminated the growth-inhibitory effect of abemaciclib, which remained highly effective in control tumors. Across all treatment arms, GPNMB-OE tumors failed to respond to CDK4/6 blockade, highlighting a strong resistance phenotype. These results identify GPNMB as a potent promoter of tumor progression and a key mediator of resistance to abemaciclib. Our findings position GPNMB as a potential biomarker and therapeutic target that may help identify patients unlikely to benefit from CDK4/6 inhibition.