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PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling

Oncogene volume 35, pages 2961–2970 (2016)Cite this article

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Abstract

Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2-positive breast cancer with coexisting PIK3CAH1047R. Induction of PIK3CAH1047R expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of phosphatidylinositol-3-kinase (PI3K)/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CAH1047R expression. Strikingly, although these Her2+ PIK3CAH1047R-initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CAH1047R, a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110a. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2-positive cancers with coexisting PIK3CA-activating mutations.

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Acknowledgements

We thank Dr Roderick Bronson and the Dana-Farber/Harvard Cancer Center Rodent Histoplathology Core for histopathological analyses. We thank L. Chodosh (University of Pennsylvania School of Medicine) for providing MMTVrtTAmice. This work was supported by the Susan G. Komen Breast Cancer Foundation CCR12225834 (HC), Susan G. Komen Breast Cancer Foundation (IEK), Breast Cancer Research Foundation (NUL, EPW and JJZ), ACS grant CRP-07-234-06-COUN (CLA), NIH grants CA187918 (TMR and JJZ), CA172461-01 (JJZ) and 1P50CA168504 (TMR, IEK, EPW, NUL and JJZ).

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Authors and Affiliations

  1. Cancer Institute, The Second Hospital of Dalian Medical University, Dalian, China

    H Cheng

  2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    H Cheng, P Liu, C Ohlson, E Xu, L Symonds, A Isabella, T M Roberts & J J Zhao

  3. Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

    W J Muller

  4. Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA

    N U Lin

  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    I E Krop & E P Winer

  6. Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA

    C L Arteaga

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Correspondence to H Cheng or J J Zhao.

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Competing interests

TM Roberts is a consultant of Novartis and has received research grant from Novartis. EP Winer has received research grants from Genentech and Roche. IE Krop is a consultant of Amgen and he has received research funding from Genentech. NU Lin has received research grants from Genentech, Array Biopharma, GlaxoSmithKline, Kadmon and Novartis. The other authors declare no conflict of interest.

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Cheng, H., Liu, P., Ohlson, C. et al. PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 35, 2961–2970 (2016). https://doi.org/10.1038/onc.2015.377

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