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 B. Mills; Jean J. Zhao

doi:10.1038/nm.2402

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 B. Mills, Jean J. Zhao

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218 Scopus citations

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 language	English (US)
Pages (from-to)	1116-1121
Number of pages	6
Journal	Nature medicine
Volume	17
Issue number	9
DOIs	https://doi.org/10.1038/nm.2402
State	Published - Sep 2011
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Liu, P., Cheng, H., Santiago, S., Raeder, M., Zhang, F., Isabella, A., Yang, J., Semaan, D. J., Chen, C., Fox, E. A., Gray, N. S., Monahan, J., Schlegel, R., Beroukhim, R., Mills, G. B., & 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

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, GB & 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

@article{ed245e65e01e483ba72c0aeb6a7bca24,

title = "Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms",

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.",

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

note = "Funding Information: 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.",

year = "2011",

month = sep,

doi = "10.1038/nm.2402",

language = "English (US)",

volume = "17",

pages = "1116--1121",

journal = "Nature medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

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T1 - Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms

AU - Liu, Pixu

AU - Cheng, Hailing

AU - Santiago, Stephanie

AU - Raeder, Maria

AU - Zhang, Fan

AU - Isabella, Adam

AU - Yang, Janet

AU - Semaan, Derek J.

AU - Chen, Changzhong

AU - Fox, Edward A.

AU - Gray, Nathanael S.

AU - Monahan, John

AU - Schlegel, Robert

AU - Beroukhim, Rameen

AU - Mills, Gordon B.

AU - Zhao, Jean J.

N1 - Funding Information: 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.

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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.

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ER -

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

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