Pharmaceutical compositions for the treatment of cancer are provided. In one embodiment the composition comprises Gamitrinib and a P13K inhibitor selected from PX-866, AZD6482, LY294002. BEZ235, GSK458, GDCO941, ZSTK474, BKM120 and GSK2636771B. Methods of treating cancer are also provided. The present invention is based in part on the inventor's discovery that combination therapy that targets mitochondria eliminates tumor adaptation induced by P13K inhibition, and improves clinical outcome in cancer.