Delahaye Celia, Figarol Sarah, Pradines Anne, Favre Gilles, Mazieres Julien, Calvayrac Olivier
Cancer Research Centre of Toulouse, INSERM UMR1037, CNRS UMR5071, UPS, 31100 Toulouse, France.
Laboratory of Medical Biology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, 31059 Toulouse, France.
Cancers (Basel). 2022 May 25;14(11):2613. doi: 10.3390/cancers14112613.
Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP.
肺癌是全球男性和女性癌症相关死亡的主要原因。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）是治疗携带EGFR激活突变的晚期非小细胞肺癌（NSCLC）患者的有效疗法，但由于不可避免地出现耐药性，并非治愈性疗法。最近的体外研究表明，对EGFR-TKI的耐药性可能源于一小部分耐药物质细胞（DTP）通过非基因重编程，进入可逆的缓慢至非增殖状态，然后才产生基因衍生的耐药性。因此，解读控制耐药物质状态动态的分子机制是为患者提供可持续治疗方案的首要任务。越来越多的关于DTP存活的分子机制被描述出来，比如染色质和表观遗传重塑、抗凋亡/存活途径的重新激活、代谢重编程以及与微环境的相互作用。在此，我们回顾并讨论了与DTP状态相关的现有机制。我们描述了它们的生物学特征、耐受的分子机制以及针对DTP进行测试的治疗策略。
