Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population.

Bhola NE, Jansen VM, Koch JP, Li H, Formisano L, Williams JA, Grandis JR, Arteaga CL
Cancer Res. 2016 76 (2): 440-52

PMID: 26676751 · PMCID: PMC4715956 · DOI:10.1158/0008-5472.CAN-15-1640-T

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.

©2015 American Association for Cancer Research.

MeSH Terms (10)

Cell Line, Tumor Drug Resistance, Neoplasm Humans Mechanistic Target of Rapamycin Complex 2 Multiprotein Complexes Neoplastic Stem Cells Signal Transduction TOR Serine-Threonine Kinases Triple Negative Breast Neoplasms Xenograft Model Antitumor Assays

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