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PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers

Oncogene volume 35, pages 3607–3612 (2016)Cite this article

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Abstract

Human epidermal growth factor receptor-2 (HER2) amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110α or p110β inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2 activation and Pten loss coupled with deletion of p110α or p110β. Ablation of p110α, but not p110β, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110α primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110β conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110α inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110β inhibitor to dual HER2 and p110α inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110α/β may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors.

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Acknowledgements

We thank Dr Roderick Bronson and the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core for histopathological analyses. MMTV-NIC mice were provided by W Muller (McGill University). Floxed Pten mice were provided by H Wu (UCLA). This work was supported by start-up fund from Department of Pathology and Laboratory Medicine, Medical University of South Carolina (QW), the Susan G. Komen Breast Cancer Foundation CCR 12225834 (IEK), the Breast Cancer Research Foundation (NUL, EPW, JJZ), NIH grants CA187918 (TMR and JJZ), CA172461-01 (JJZ) and 1P50CA168504 (TMR, IEK, EPW, NUL and JJZ).

Author information

Author notes

  1. Q Wang

    Present address: 5Current address: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.,

  2. Q Wang and P Liu: These authors contributed equally to this work.

Authors and Affiliations

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

    Q Wang, P Liu, J M Spangle, T Von, T M Roberts & J J Zhao

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Q Wang, J M Spangle, T Von, T M Roberts & J J Zhao

  3. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    P Liu

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

    N U Lin, I E Krop & E P Winer

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  1. Q Wang
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Corresponding author

Correspondence to J J Zhao.

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Competing interests

TMR is a consultant of Novartis and has received a research grant from Novartis. EPW has received research grants from Genentech and Roche. IEK is a consultant of Amgen and has received research funding from Genentech. NUL has received research grants from Genentech, Array Biopharma, GlaxoSmithKline, Kadmon and Novartis. The remaining authors declare no competing financial interest.

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Wang, Q., Liu, P., Spangle, J. et al. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 35, 3607–3612 (2016). https://doi.org/10.1038/onc.2015.406

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