Abstract
Germline pathogenic variants in the CDH1 gene, coding for E-cadherin protein, cause inherited diffuse gastric cancer and lobular breast cancer; chemoprevention strategies are needed. Our aim is to prevent early diffuse gastric cancer by targeting E-cadherin-deficient cells using combination therapies. This approach will prevent the need for a prophylactic gastrectomy and mastectomy for pathogenic variant carriers.
This study investigates synergistic vulnerabilities in CDH1-deficient cells combining statins (fluvastatin, pitavastatin) with AKT inhibitors (miransertib, capivasertib). Dose-response curves and fixed-dose combinations revealed synergistic synthetic lethality. Particularly with fluvastatin + miransertib and fluvastatin + capivasertib. Similar synergy was also observed with pitavastatin, a strong candidate for chemoprevention due to its high bioavailability. Pitavastatin was also tested with nelfinavir and dipyridamole to enhance statin efficacy through SREBP2 inhibition, showing synthetic lethality and synergy at higher doses, suggesting potential for triple-drug strategies.
Western blotting revealed increased cleaved SREBP2 in both statin-AKT inhibitor combinations, implicating mevalonate pathway activation, while AKT signalling decreased consistently. Flow cytometry showed elevated apoptosis in combination-treated cells versus controls, however, though sublethal doses did not significantly differ between WT and CDH1-deficicent cells, supporting selective targeting while preserving normal cell viability.
These results suggest that combining statins with an AKT inhibitor represents a promising chemoprevention strategy for E-cadherin-deficient gastric cancers. Future work will validate these findings in gastric organoids derived from our mouse model, both with and without E-cadherin, to provide a physiologically relevant preclinical model.