ARTICLE | Distillery Therapeutics

Therapeutics: Phosphoinositide 3-kinase α (PI3Kα); pyruvate dehydrogenase kinase 1 (PDK1); serum/glucocorticoid regulated kinase 1 (SGK1)

August 18, 2016 7:00 AM UTC

Patient sample, cell culture and mouse studies suggest inhibiting PDK1 or SGK1 could help treat PI3Kα inhibitor-resistant breast cancer. In breast cancer patients, high tumor expression of SGK1 correlated with resistance to chemotherapy. In human PI3Kα inhibitor-resistant breast cancer cell lines, shRNA targeting PDK1 or SGK1, or an SGK1 inhibitor tool compound, increased sensitivity to the PI3Kα inhibitor alpelisib compared with a scrambled shRNA or vehicle. In a xenograft mouse model of PI3Kα inhibitor-resistant breast cancer, alpelisib plus shRNA targeting PDK1 or SGK1, alpelisib plus a PDK1 inhibitor tool compound, or alpelisib plus the SGK1 inhibitor decreased tumor growth compared with any agent alone. Next steps could include identifying and testing small molecule inhibitors of PDK1 and SGK1 in animal models of various PI3Kα inhibitor-resistant cancers...