Metformin and erlotinib synergize to inhibit basal breast cancer

Ying Ka Ingar Lau, Xing Du, Vinayak Rayannavar, Benjamin Hopkins, Jacquelyn Shaw, Eliana Bessler, Tiffany Thomas, Maira M. Pires, Megan Keniry, Ramon E. Parsons, Serge Cremers, Matthias Szabolcs, Matthew A. Maurer

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth. Our data with other compounds suggested that biguanides combined with EGFR inhibitors have the potential to outperform other targeted drug combinations and could be employed in other breast cancer subtypes, as well as other tumor types, with activated EGFR and PI3K signaling. Analysis of BBC cell line alterations led to the hypothesis that loss of PTEN sensitized cells to the drug combination which was confirmed usingisogenic cell line models with and without PTEN expression. Combined metformin and erlotinib led to partial regression of PTEN-null and EGFR-amplified xenografted MDAMB- 468 BBC tumors with evidence of significant apoptosis, reduction of EGFR and AKT signaling, and lack of altered plasma insulin levels. Combined treatment also inhibited xenografted PTEN null HCC-70 BBC cells. Measurement of trough plasma drug levels in xenografted mice and a separately performed pharmacokinetics modeling study support possible clinical translation.

Original languageEnglish
Pages (from-to)10503-10517
Number of pages15
JournalOncotarget
Volume5
Issue number21
DOIs
StatePublished - 2014

Keywords

  • Breast cancer
  • EGFR
  • Erlotinib
  • Metformin
  • PTEN

Fingerprint

Dive into the research topics of 'Metformin and erlotinib synergize to inhibit basal breast cancer'. Together they form a unique fingerprint.

Cite this