NDLI: Metformin and erlotinib synergize to inhibit basal breast cancer

Content Provider	PubMed Central
Author	Lau, Ying-ka Ingar Du, Xing Vinayak, Reyannavar Hopkins, Benjamin Shaw, Jacquelyn Bessler, Eliana Thomas, Tiffany Pires, Maira M. Keniry, Megan Parsons, Ramon E. Cremers, Serge Matthias, Szabolcs Maurer, Matthew A.
Copyright Year	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.
Ending Page	10517
Starting Page	10503
File Format	PDF
ISSN	19492553
e-ISSN	19492553
Journal	Oncotarget
Issue Number	21
Volume Number	5
Language	English
Publisher	Impact Journals LLC
Publisher Date	2014-11-01
Access Restriction	Open
Rights Holder	Impact Journals LLC
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Oncology

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