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.

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

“…MDA-MB-468, MDA-MB-157, MDA-MB-435S, MDA-MB-436, MDA-MB-231, MX-1, MCF7, BT20, L56Br-C1, CAOV-3, HCC1143, HCC1806, HCC1937, HCC1987, HCC70, HCC38, BT549, mice implanted with MDA-MB-468 cells into the mammary fat pad [186] Everolimus Metformin-induced additive effects were observed when used as a co-treatment with everolimus and inhibited cell proliferation and colony formation ability. The additive effect of the combinatorial treatment was also related to the inhibition of mitochondrial respiration and mTOR growth signaling.…”

Estrogen Receptor-β and the Insulin-Like Growth Factor Axis as Potential Therapeutic Targets for Triple-Negative Breast Cancer

“…At physiologic or low levels of glucose, the ability of metformin to inhibit cell proliferation and tumor formation, and induce apoptosis is optimized. 137,138 Metformin induces apoptosis of TNBC. Although not completely understood, metformin mediates this process by activating miR-193b, an inhibitor of fatty acid synthase, and AMP-activated protein kinase (AMPK), which inhibits signaling by mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription-3 (STAT-3).…”

“…Lau et al found that basal breast cancer responds well to metformin and erlotinib. 137 A combination of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, and inhibition of activation of sphingosine kinase-1 (SphK1)/sphingosine 1-phosphate (S1P) system by IGFBP-3 prevented TNBC tumor growth. 148 To prevent metastasis, Mancini et al 79 investigated the efficacy of co-targeting IGF1 and IGF-2, and their receptors.…”

Metformin‐sensitized NSCLC cells to osimertinib via AMPK‐dependent autophagy inhibition

“…Metformin is available generically hypoglycaemic agents but also has been shown to play an efficient role against different types of cancer, alone or in combination with other drugs such as first‐generation EGFR‐TKIs . We recently reported that metformin‐based combinatorial therapy effectively blocked the growth of TKI‐resistant cancer cells via apoptosis induction and autophagy inhibition .…”