Investigating the role of TRPM4 in the cancer cell death induced by ErSO and derivatives

The majority of breast cancers (BC) are hormone receptor positive (HR+/HER2-), and there remains a significant unmet need for alternative therapeutics for patients who become resistant to or no longer respond to endocrine therapy. Endocrine therapies primarily target estrogen receptor alpha (ERalpha) to inhibit tumor growth; however, acquired resistance and ERalpha mutations often limit the long-term efficacy of these treatments. Alternative therapeutic strategies that do not rely on endocrine pathways are critical for managing unresponsive breast cancers. Transient receptor potential cation channel subfamily M member 4 (TRPM4) is a calcium-activated monovalent ion channel that has emerged as a promising non-endocrine target in oncology. We have discovered a compound, called ErSO-TFPy, with potent cytotoxicity against TRPM4-positive (TRPM4+) cancer cells via a novel non-apoptotic mechanism. Notably, elevated TRPM4 expression correlates with increased sensitivity to ErSO-TFPy. To investigate the role of TRPM4 in the cell death induced by ErSO-TFPy, we performed studies including cellular thermal shift assays (CETSA) and cellular probe colocalizations. To assess the possibility of leveraging TRPM4 activation as a selective anticancer strategy, we looked at TRPM4 mutations, subcellular localization, temperature sensitivity, and cell viability in response to ErSO-TFPy and related compounds. Our data suggests TRPM4 plays a key role in the cell death induced by ErSO-TFPy.