Cancer

Cell culture and mouse studies suggest inhibiting GSK3 could help treat KRAS-driven pancreatic, colon and lung cancers. Screening of a library of 304 kinase inhibitors in cell-based growth assays yielded a GSK3 inhibitor tool compound that inhibited growth with 45-fold greater potency in a KRAS-driven human pancreatic cancer cell line than in a KRAS-independent human lung cancer cell line (IC₅₀ values of 0.4 μM and 18 μM, respectively). In KRAS-driven human cancer cell lines - two pancreatic, one colorectal and one lung cancer - the GSK3 inhibitor or an siRNA targeting GSK3 increased markers of apoptosis and decreased viability compared with no treatment or a non-specific siRNA, respectively. In a mouse model of KRAS-driven pancreatic cancer, the GSK3 inhibitor or the siRNA targeting GSK3 decreased tumor growth compared with vehicle or the non-specific siRNA, respectively. In three KRAS-driven patient-derived xenograft (PDX) mouse models of pancreatic cancer, the GSK3 inhibitor decreased tumor growth compared with vehicle. Next steps could include testing the compound in mouse models of other KRAS-driven cancers...