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

H. Cheng, P. Liu, C. Ohlson, E. Xu, L. Symonds, A. Isabella, W. J. Muller, N. U. Lin, I. E. Krop, T. M. Roberts, E. P. Winer, C. L. Arteaga, J. J. Zhao

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2961-2970
Number of pages10
JournalOncogene
Volume35
Issue number23
DOIs
StatePublished - Jun 9 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Cheng, H., Liu, P., Ohlson, C., Xu, E., Symonds, L., Isabella, A., Muller, W. J., Lin, N. U., Krop, I. E., Roberts, T. M., Winer, E. P., Arteaga, C. L., & Zhao, J. J. (2016). PIK3CAH1047R - And Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene, 35(23), 2961-2970. https://doi.org/10.1038/onc.2015.377