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

Pixu Liu, Hailing Cheng, Stephanie Santiago, Maria Raeder, Fan Zhang, Adam Isabella, Janet Yang, Derek J. Semaan, Changzhong Chen, Edward A. Fox, Nathanael S. Gray, John Monahan, Robert Schlegel, Rameen Beroukhim, Gordon Mills, Jean J. Zhao

Research output: Contribution to journalArticle

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Abstract

PIK3CA gain-of-function mutations are a common oncogenic event in human malignancy, 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 PIK3CA H1047R. Notably, most PIK3CA H1047R-driven mammary tumors recurred after PIK3CA H1047R 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.

Original languageEnglish (US)
Pages (from-to)1116-1121
Number of pages6
JournalNature Medicine
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2011
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Tumors
Breast Neoplasms
Amplification
Neoplasms
Mutation
Therapeutics
Treatment Failure
Oncogenes
Chemical activation
Survival

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Liu, P., Cheng, H., Santiago, S., Raeder, M., Zhang, F., Isabella, A., ... Zhao, J. J. (2011). Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nature Medicine, 17(9), 1116-1121. https://doi.org/10.1038/nm.2402

Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. / Liu, Pixu; Cheng, Hailing; Santiago, Stephanie; Raeder, Maria; Zhang, Fan; Isabella, Adam; Yang, Janet; Semaan, Derek J.; Chen, Changzhong; Fox, Edward A.; Gray, Nathanael S.; Monahan, John; Schlegel, Robert; Beroukhim, Rameen; Mills, Gordon; Zhao, Jean J.

In: Nature Medicine, Vol. 17, No. 9, 01.09.2011, p. 1116-1121.

Research output: Contribution to journalArticle

Liu, P, Cheng, H, Santiago, S, Raeder, M, Zhang, F, Isabella, A, Yang, J, Semaan, DJ, Chen, C, Fox, EA, Gray, NS, Monahan, J, Schlegel, R, Beroukhim, R, Mills, G & Zhao, JJ 2011, 'Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms', Nature Medicine, vol. 17, no. 9, pp. 1116-1121. https://doi.org/10.1038/nm.2402
Liu, Pixu ; Cheng, Hailing ; Santiago, Stephanie ; Raeder, Maria ; Zhang, Fan ; Isabella, Adam ; Yang, Janet ; Semaan, Derek J. ; Chen, Changzhong ; Fox, Edward A. ; Gray, Nathanael S. ; Monahan, John ; Schlegel, Robert ; Beroukhim, Rameen ; Mills, Gordon ; Zhao, Jean J. / Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. In: Nature Medicine. 2011 ; Vol. 17, No. 9. pp. 1116-1121.
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