Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and -independent mechanisms

PIK3CA gain-of-function mutations are a common oncogenic event in human malignancy(1–4), making PI3K an attractive target for cancer therapy. Despite the great promise of targeted therapy, resistance often develops, resulting in treatment failure. To elucidate mechanisms of resistance to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing human PIK3CA(H1047R). Surprisingly, most PIK3CA(H1047R)-driven mammary tumors recurred following PIK3CA(H1047R) inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including focal amplification of c-Met or c-Myc. While c-Met amplification allowed tumor survival dependent on activation of endogenous PI3K, tumors with c-Myc amplification became independent of the PI3K pathway. Functional analyses demonstrated that c-Myc contributed to oncogene independence and resistance to PI3K inhibition. Importantly, PI3KCA mutations and increased c-MYC levels co-occur in a substantial fraction of human breast tumors. Together, these data suggest that c-MYC elevation represents a potential mechanism by which tumors develop resistance to current PI3K-targeted therapies.