Metformin has been suggested as an anti-cancer agent. However, increasing reports show that some tumors are resistant to metformin. Identification of factors affecting metformin mediated cancer therapy is of great significance. FGFR1 is a receptor-tyrosine-kinase that is frequently overexpressed in breast cancer, which is associated with poor-prognosis. To investigate the effect of FGFR1 overexpression on metformin-induced inhibition of breast cancer cells, we demonstrated that FGFR1 overexpression rendered MCF-7 and T47D cells resistant to metformin. In particular, we found that, in addition to AKT and ERK1/2 activation, FGFR1-induced activation of IRS1 and IGF1R, key regulators connecting metabolism and cancer, was associated with metformin resistance. Targeting IRS with IRS1 KO or IRS inhibitor NT157 significantly sensitized FGFR1 overexpressing cells to metformin. Combination of NT157 with metformin induced enhanced inhibition of p-IGF1R, p-ERK1/2 and p-mTOR. Moreover, we demonstrated that IRS1 functions as a critical mediator of the crosstalk between FGFR1 and IGF1R pathways, which involves a feedback loop between IRS1 and MAPK/ERK. Our study highlights the significance of FGFR1 status and IRS1 activation in metformin-resistance, which will facilitate the development of strategies targeting FGFR overexpression-associated metformin resistance.

已建议二甲双胍作为抗癌药。但是，越来越多的报道表明某些肿瘤对二甲双胍有抗药性。识别影响二甲双胍介导的癌症治疗的因素具有重要意义。FGFR1是一种酪氨酸激酶受体，在乳腺癌中经常过表达，与预后不良有关。为了研究FGFR1过表达对二甲双胍诱导的乳腺癌细胞抑制的影响，我们证明了FGFR1过表达使MCF-7和T47D细胞对二甲双胍具有抗性。特别是，我们发现，除了AKT和ERK1 / 2激活外，FGFR1诱导的IRS1和IGF1R（连接代谢和癌症的关键调节剂）的激活与二甲双胍耐药有关。用IRS1 KO或IRS抑制剂NT157靶向IRS可显着使过表达FGFR1的细胞对二甲双胍敏感。NT157与二甲双胍的组合可增强对p-IGF1R，p-ERK1 / 2和p-mTOR的抑制作用。此外，我们证明了IRS1是FGFR1和IGF1R通路之间串扰的关键介体，它涉及IRS1和MAPK / ERK之间的反馈回路。我们的研究强调了FGFR1状态和IRS1激活对二甲双胍耐药性的重要性，这将促进针对FGFR过表达相关的二甲双胍耐药性策略的发展。这涉及IRS1和MAPK / ERK之间的反馈回路。我们的研究强调了FGFR1状态和IRS1激活对二甲双胍耐药性的重要性，这将促进针对FGFR过表达相关的二甲双胍耐药性策略的发展。这涉及IRS1和MAPK / ERK之间的反馈回路。我们的研究强调了FGFR1状态和IRS1激活对二甲双胍耐药性的重要性，这将促进针对FGFR过表达相关的二甲双胍耐药性策略的发展。