title: Metformin and erlotinib synergize to inhibit basal breast cancer.
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.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
authors.forename: Ying-Ka Ingar
authors.initials: YK
authors.lastname: Lau
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
authors.forename: Xing
authors.initials: X
authors.lastname: Du
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
authors.forename: Vinayak
authors.initials: V
authors.lastname: Rayannavar
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hopkins
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032. Current address, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Shaw
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
authors.forename: Eliana
authors.initials: E
authors.lastname: Bessler
authors.affiliation: Irving Institute for Clinical and Translational Research, Columbia University, New York, NY 10032.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Maira M
authors.initials: MM
authors.lastname: Pires
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY 10029. Current address, Biology Department, University of Texas Pan American, Edinburg, TX 78539.
authors.forename: Megan
authors.initials: M
authors.lastname: Keniry
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ramon E
authors.initials: RE
authors.lastname: Parsons
authors.affiliation: Irving Institute for Clinical and Translational Research, Columbia University, New York, NY 10032.
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.affiliation: Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032. Department of Medicine, Columbia University, New York, NY 10032.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Maurer
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D007004:Hypoglycemic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D008687:Metformin; D000069347:Erlotinib Hydrochloride; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human