Abstract 4758: Targeting cellular pH as a novel therapeutic strategy in CDK4/6 inhibitor resistant breast cancer

Abstract Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i) are part of standard of care therapy in combination with antiestrogens for the treatment of metastatic estrogen receptor positive (ER+) breast cancer. Of the three major CDK4/6i, only ribociclib and abemaciclib, but not palbociclib, have shown significant improvement in overall survival in the clinic. However, resistance to CDK4/6i is prevalent and advanced metastatic ER+ breast cancer remains incurable. Other studies have focused on cell cycle or growth factor alterations in resistant tumors but targeting these pathways have not been clinically validated. Beside inhibiting the cell cycle, CDK4/6i are known to induce lysosomes in sensitive cells but the role of lysosomes in CDK4/6i resistance remains elusive. Recently, we have shown that CDK4/6i resistant breast cancer cells gain metastatic potential relative to sensitive cells and this is potentially due to deregulated lysosomes, which can be targeted with lysosome destabilizers. Here we show that all three CDK4/6i induce rapid lysosomal acidification in sensitive cells, which suggests a role of cellular pH in CDK4/6i-mediated cell death. However, in resistant cells, lysosomal acidification following CDK4/6i treatment was diminished. Therefore, we hypothesize that cellular pH is tightly regulated in CDK4/6i resistant cells and this pathway can be targeted to inhibit cell viability. Interestingly, protein levels of carbonic anhydrase IX (CA9), an important regulator of cellular pH, is significantly elevated in resistant cells. Increased CA9 levels correlate with impaired overall survival in breast and other cancers. Small molecule inhibitor of CA9, S4 or clinical-grade SLC-0111, inhibits growth of resistant cells when combined with CDK4/6i plus antiestrogens. Thus, our study highlights the role of pH changes in CDK4/6i resistant breast cancer and offer therapeutic strategies to treat this incurable disease. Citation Format: Erin R. Scheidemann, Diane M. Demas, Ayesha N. Shajahan-Haq. Targeting cellular pH as a novel therapeutic strategy in CDK4/6 inhibitor resistant breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4758.