Metformin and erlotinib synergize to inhibit basal breast cancer

Abstract

// Ying-Ka Ingar Lau 1 , Xing Du 1 , Vinayak Rayannavar 1 , Benjamin Hopkins 3 , Jacquelyn Shaw 1, 4 , Eliana Bessler 1 , Tiffany Thomas 5 , Maira M. Pires 3 , Megan Keniry 3, 6 , Ramon E. Parsons 3 , Serge Cremers 5 , Matthias Szabolcs 7 , Matthew A. Maurer 1, 2 1 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032 2 Department of Medicine, Columbia University, New York, NY 10032 3 Icahn School of Medicine at Mount Sinai, New York, NY 10029 4 Current address, Albert Einstein College of Medicine, Bronx, NY 10461 5 Irving Institute for Clinical and Translational Research, Columbia University, New York, NY 10032 6 Current address, Biology Department, University of Texas Pan American, Edinburg, TX 78539 7 Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032 Correspondence to: Matthew A. Maurer, e-mail: mm2058@columbia.edu Keywords: breast cancer, metformin, erlotinib, PTEN, EGFR Received: July 11, 2014      Accepted: August 21, 2014      Published: November 04, 2014 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 using isogenic cell line models with and without PTEN expression. Combined metformin and erlotinib led to partial regression of PTEN-null and EGFR-amplified xenografted MDA-MB-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.