Treatment of triple-negative breast cancer with TORC1/2 inhibitors sustains a drug-resistant and notch-dependent cancer stem cell population

Neil E. Bhola, Valerie M. Jansen, James P. Koch, Hua Li, Luigi Formisano, Janice A. Williams, Jennifer R. Grandis, Carlos L. Arteaga

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition of this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 inhibition is driven by cancer stem cell (CSC)-like populations that could be targeted to enhance the antitumor action of these drugs. Therefore, we investigated the molecular mechanisms by which PI3K/mTOR inhibitors affect the stem-like properties of TNBC cells. Treatment of established TNBC cell lines with a PI3K/mTOR inhibitor or a TORC1/2 inhibitor increased the expression of CSC markers and mammosphere formation. A CSC-specific PCR array revealed that inhibition of TORC1/2 increased FGF1 and Notch1 expression. Notch1 activity was also induced in TNBC cells treated with TORC1/2 inhibitors and associated with increased mitochondrial metabolism and FGFR1 signaling. Notably, genetic and pharmacologic blockade of Notch1 abrogated the increase in CSC markers, mammosphere formation, and in vivo tumor-initiating capacity induced by TORC1/2 inhibition. These results suggest that targeting the FGFR-mitochondrial metabolism-Notch1 axis prevents resistance to TORC1/2 inhibitors by eradicating drug-resistant CSCs in TNBC, and may thus represent an attractive therapeutic strategy to improve drug responsiveness and efficacy.

Original languageEnglish (US)
Pages (from-to)440-452
Number of pages13
JournalCancer research
Volume76
Issue number2
DOIs
StatePublished - Jan 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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