Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells

Todd W. Miller, James T. Forbes, Chirayu Shah, Shelby K. Wyatt, H. Charles Manning, Maria G. Olivares, Violeta Sanchez, Teresa C. Dugger, Nara De Matos Granja, Archana Narasanna, Rebecca S. Cook, J. Phillip Kennedy, Craig W. Lindsley, Carlos L. Arteaga

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

Purpose: A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mammalian target of rapamycin (mTOR) is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab. Experimental Design: Immunocompetent mice bearing HER2+ mammary tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the combination. Mice were imaged for tumor cell death using an optical Annexin-V probe and with [18F] FDG positron emission tomography. The signaling and growth effects of the mTOR inhibitor RAD001 on HER2+ cells treated with trastuzumab or lapatinib were evaluated. Results: Treatment of mice with trastuzumab plus rapamycin was more effective than single-agent treatments, inducing complete regression of 26 of 26 tumors. The combination induced tumor cell death (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor cell proliferation as determined by phosphorylated S6 and Ki-67 immunohistochemistry, respectively. In culture, the combination of RAD001 plus trastuzumab inhibited cell growth more effectively than either drug alone. Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 resulted in HER2-independent activation of mTOR and dampened the response to trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased phosphorylated S6 and growth in TSC2-expressing cells but not in TSC2-knockdown cells. Conclusions: Inhibition of PI3K and mTOR are required for the growth-inhibitory effect of HER2 antagonists. These findings collectively support the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2+ breast cancer.

Original languageEnglish (US)
Pages (from-to)7266-7276
Number of pages11
JournalClinical Cancer Research
Volume15
Issue number23
DOIs
StatePublished - Dec 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Miller, T. W., Forbes, J. T., Shah, C., Wyatt, S. K., Manning, H. C., Olivares, M. G., Sanchez, V., Dugger, T. C., Granja, N. D. M., Narasanna, A., Cook, R. S., Kennedy, J. P., Lindsley, C. W., & Arteaga, C. L. (2009). Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clinical Cancer Research, 15(23), 7266-7276. https://doi.org/10.1158/1078-0432.CCR-09-1665