Abstract PD03-05: A Novel Combination Therapy for Triple Negative Breast Cancer: Erlotinib and Metformin

Abstract

Abstract Background: Triple negative breast cancer (TNBC) is defined by lack of expression of estrogen, progesterone and HER2 receptors and accounts for approximately 15% of breast cancer. TNBC patients have a poor prognosis and novel therapies are needed. The majority of TNBC are basal-like tumors that overexpress the epidermal growth factor receptor (EGFR). However, clinical use of EGFR inhibitors has yielded disappointing results likely due, in part, to downstream driving mutations including PTEN. TNBC occurs more frequently in type II diabetic patients indicating that aberrations in glucose metabolism may contribute to TNBC development. The type II diabetes drug metformin has been associated with a decreased incidence of breast cancer and enhanced response to chemotherapy. In this study, we explored the combined effect of erlotinib (an EGFR kinase inhibitor) and metformin on TNBC. Results and Methods: Using the TNBC cell lines MDA-MB-468 and BT549 with known p53 mutation, PTEN mutation and EGFR expression, we observed the novel combination of metformin and erlotinib potently induced cell death in these TNBC cell lines in a 6-day proliferation assay. Using metformin or erlotinib alone at the same doses partially inhibited growth but was unable to induce cell death. In a cytotoxic clonogenic assay, erlotinib combined with metformin significantly suppressed formation of colonies compared with either drug alone, and compared with the TORC1 inhibitor rapamycin combined with erlotinib or metformin. In addition, as compared with control MCF10A cells (an immortalized nontransformed human mammary epithelial cell line), the combined treatment preferentially induced cell death in an MCF10A cell line modified with PTEN loss, expression of dominant negative p53 and increased expression of EGFR. Again, cell death was not observed when either drug was used alone. We showed through western blots that erlotinib as a single agent is very effective in down-regulating the activity of the MAPK pathway but is less effective in down-regulating the activity of the PI3K pathway. We demonstrated that metformin and erlotinib together potentiate the inhibition of AKT and downstream S6 ribosomal protein which might be one of the mechanisms contributing to the observed synergy of the drugs. Discussion: A significant subset of TNBC expresses EGFR, has PTEN loss and mutated p53. This recurrent set of lesions possibly leads to a unique and aberrant signaling and metabolic signature that confers TNBC an advantage for survival. We demonstrated that erlotinib and metformin act synergistically to remove this survival advantage in basal breast cancer cell lines while having minimal effect on normal epithelial breast cells. This drug combination potently down-regulates both the MAPK and PI3K pathways which are often aberrantly activated in basal-like breast tumors. Our results provide a rationale for the continued assessment of combining EGFR inhibitors with metformin in the treatment of TNBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-05.