Document Type
Article
Publication Date
11-2014
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 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.
Recommended Citation
Lau, Y.-K. I., Du, X., Rayannavar, V., Hopkins, B., Shaw, J., Bessler, E., Thomas, T., Pires, M. M., Keniry, M., Parsons, R. E., Cremers, S., Szabolcs, M., & Maurer, M. A. (2014). Metformin and erlotinib synergize to inhibit basal breast cancer. Oncotarget, 5(21), 10503–10517. https://doi.org/10.18632/oncotarget.2391
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
First Page
10503
Last Page
10517
Publication Title
Oncotarget
DOI
10.18632/oncotarget.2391
Comments
Original published version available at https://doi.org/10.18632/oncotarget.2391