综上所述，研究人员在实验中发现，肿瘤相关成纤维细胞对肺癌细胞药物反应的影响因肺癌亚型和药物的不同而不同。对于EGFR突变型肺癌，CAF旁分泌的促癌细胞因子IGF减少，抗癌蛋白IGFBP增多，减弱了对IGF1R和整合素的激活，抑制了IGF1R介导的IRS2/AKT信号和整合素介导的FAK/ERK信号，从而增强EGFR抑制剂的药效。

研究人员还以CAF促药敏的机制为靶标，证明了在抑制EGFR的同时靶向IGF1R和FAK的联合用药对于EGFR突变肺癌的卓越疗效。

这项研究不仅加深了我们对CAF在肿瘤微环境中的作用的理解，还提出了一个消除肺癌耐药的治疗策略，有望为EGFR抑制剂在临床中的应用打开一个新的局面。

参考文献

[1]Warth A, Penzel R, Lindenmaier H, et al. EGFR, KRAS, BRAF and ALK gene alterations in lung adenocarcinomas: patient outcome, interplay with morphology and immunophenotype. Eur Respir J. 2014;43(3):872-883. doi:10.1183/09031936.00018013

[2]Rotow J, Bivona TG. Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer. 2017;17(11):637-658. doi:10.1038/nrc.2017.84

[3]Chen C, Hou J, Yu S, et al. Role of cancer-associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non-small cell lung cancer. Oncol Lett. 2021;21(5):413. doi:10.3892/ol.2021.12674

[4]Remsing Rix LL, Sumi NJ, Hu Q, et al. IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells. Sci Signal. 2022;15(747):eabj5879. doi:10.1126/scisignal.abj5879

[5]Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17(1):53. Published 2018 Feb 19. doi:10.1186/s12943-018-0793-1

[6]Landis J, Shaw LM. Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3 to regulate aerobic glycolysis. J Biol Chem. 2014;289(26):18603-18613. doi:10.1074/jbc.M114.564070

[7]Li X, Liu J, Sun H, et al. SRPX2 promotes cell proliferation and invasion via activating FAK/SRC/ERK pathway in non-small cell lung cancer. Acta Biochim Pol. 2020;67(2):165-172. doi:10.18388/abp.2020_5158