Abstract
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.
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Acknowledgements
We thank T. Roberts, L. Cantley and W. Sellers for scientific discussions and suggestions. We thank L. Clayton and D. Silver for critical review of this manuscript. We thank R. Bronson for pathological analyses of tumor samples. We thank C. Li and E. Allgood for technical assistance. We thank L. Chodosh (University of Pennsylvania School of Medicine) for providing MMTV-rtTA mice. This work was supported by US National Institutes of Health grants CA134502 (J.J.Z.), CA148164-01 (J.J.Z. and N.S.G.) and K08CA122833 (R.B.), Stand Up To Cancer (J.J.Z. and G.B.M.), Dana Farber Harvard Cancer Center breast cancer SPORE grant P50 CA089393-08S1 (J.J.Z.), the US Department of Defense (BC051565 to J.J.Z.), the V Foundation (J.J.Z. and R.B.) and the Claudia Barr Program (J.J.Z.). In compliance with Harvard Medical School guidelines, we disclose that J.J.Z. and R.B. are consultants for Novartis Pharmaceuticals.
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P.L., H.C. and J.J.Z. designed the experiments, interpreted the data and wrote the paper. P.L. and H.C. carried out most of the experiments. S.S., A.I. and D.J.S. assisted with biochemical analyses and mouse work. J.Y., C.C., E.A.F., J.M. and R.S. carried out genome-wide DNA copy number profiling. N.S.G. provided GDC-0941 inhibitor. M.R. and R.B. analyzed co-occurrence of PIK3CA mutation with c-MYC amplification and overexpression in human breast tumors. F.Z. and G.B.M. provided the reverse-phase protein array data on the co-occurrence of PIK3CA mutation with increased c-MYC expression in human breast tumors.
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Liu, P., Cheng, H., Santiago, S. et al. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway–dependent and PI3K pathway–independent mechanisms. Nat Med 17, 1116–1120 (2011). https://doi.org/10.1038/nm.2402
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DOI: https://doi.org/10.1038/nm.2402
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