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PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling

Oncogene volume 34, pages 2061–2071 (2015)Cite this article

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Abstract

Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, the BCl-2-associated death promoter, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.

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Acknowledgements

We wish to thank Drs Ines Luis, Nancy Lin and Eric Winer for assistance in obtaining patient tissue samples. This work was supported by the Department of Defense Grant W81XWH-10-1-0575 and the Komen Grant CCR13262292 (to SEM), by the Breast Cancer Research Foundation (to ZCW), and by the NIH grants R01 CA130988, U01 CA176058 and U54 CA112962 (to WCH).

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Authors and Affiliations

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

    S E Moody, A C Schinzel, S Singh, F Izzo, M R Strickland, L Luo & W C Hahn

  2. Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA

    S E Moody, L Luo & W C Hahn

  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    S E Moody, S R Thomas, J S Boehm & W C Hahn

  4. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA,

    S Y Kim

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

    Z C Wang

  6. Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Z C Wang

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Correspondence to W C Hahn.

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Competing interests

SEM receives consulting fees from N-of-One Therapeutics. WCH receives consulting fees from Novartis, Blueprint Medicines and Thermo Fisher. The Hahn laboratory receives research support from Novartis. The remaining authors declare no conflict of interest.

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Moody, S., Schinzel, A., Singh, S. et al. PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling. Oncogene 34, 2061–2071 (2015). https://doi.org/10.1038/onc.2014.153

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