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

PI3K alterations are well-established drivers of breast cancer. However, PI3K-targeted therapy often results in treatment resistance and recurrence. By modeling PI3K tumorigenesis and inactivation in mice, this report shows that resistance may arise from alternative activation of the PI3K signaling pathway or by acquired alterations in other oncogenic drivers. As these mechanisms are also present in human tumors, they could be useful indicators to monitor and improve treatment responses. PIK3CA gain-of-function mutations are a common oncogenic event in human malignancy1,2,3,4, making phosphatidylinositol 3-kinase (PI3K) a target for cancer therapy. Despite the promise of targeted therapy, resistance often develops, leading to treatment failure. To elucidate mechanisms of resistance to PI3K-targeted therapy, we constructed a mouse model of breast cancer conditionally expressing human PIK3CAH1047R. Notably, most PIK3CAH1047R-driven mammary tumors recurred after PIK3CAH1047R inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including focal amplification of Met or Myc (also known as c-Met and c-Myc, respectively). Whereas Met amplification led to tumor survival dependent on activation of endogenous PI3K, tumors with Myc amplification became independent of the PI3K pathway. Functional analyses showed that Myc contributed to oncogene independence and resistance to PI3K inhibition. Notably, PIK3CA mutations and c-MYC elevation 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.