Abstract
Palbociclib, a CDK4/6 inhibitor, plays a crucial role in the treatment of HR+ breast cancer. However, resistance to palbociclib is a significant concern that merits further investigation. Our investigation identifies TMEM45A as a potential driver of palbociclib resistance and its association with increased cellular glycolysis. We demonstrate that TMEM45A is highly expressed in palbociclib-resistant breast cancer (BRCA) cells, correlating with enhanced tumor progression. Silencing TMEM45A enhances sensitivity to palbociclib, promotes cell cycle arrest and apoptosis, and inhibits the proliferation of BRCA cells. Moreover, attenuation of TMEM45A expression reduces cancer aggressiveness by decreasing the expression of EMT and glycolysis-related proteins. Subsequent gene set enrichment analysis (GSEA) confirms that TMEM45A activates the AKT/mTOR signaling pathway, which is integral to cell cycle progression and glycolysis. In a cell line-derived xenograft (CDX) mouse model, TMEM45A knockdown significantly restores sensitivity to palbociclib and suppresses tumor growth. Additionally, the use of engineered exosomes loaded with siRNA targeting TMEM45A presents a promising strategy for enhancing CDK4/6 inhibitor sensitivity without observable toxic side effects in a patient-derived xenograft (PDX) model. Collectively, our findings suggest that TMEM45A may be a therapeutic target for overcoming palbociclib resistance, and exosomal siRNA delivery could be a viable strategy for precision medicine in HR+ breast cancer.