小细胞肺癌（SCLC）是一种侵袭性的神经内分泌癌症，患者的总体存活率令人痛心，不到5％（Zimmerman等人，J Thor Oncol 14:768-83，2019）。患者通常对铂类双联化疗有反应，但几乎普遍出现药物耐药性复发。在SCLC中，高表达MYC是常见的，已与铂类耐药性相关联。本研究评估了MYC促进铂类耐药性的能力，并通过筛选鉴定出一种能够降低MYC表达并克服耐药性的药物。评估了获得铂类耐药性后体外和体内的MYC高表达。此外，在SCLC细胞系和在表达MYC特异性的肺肿瘤小鼠模型中，定义了强制MYC表达促进铂类耐药性的能力。采用高通量药物筛选法鉴定能够杀死MYC表达和铂类耐药的细胞系的药物。在移植模型中使用细胞系和患者来源的异体移植物以及在质子耐药性SCLC的自生小鼠模型中与铂类和依托泊苷化疗联合应用，定义了该药物治疗SCLC的能力。MYC表达在获得铂类耐药性后升高，而持续高表达的MYC表达促进铂类耐药性。我们展示了fimepinostat降低MYC表达，并且其在体内外是治疗SCLC的有效单一治疗剂量。实际上，fimepinostat在体内与铂类-依托泊苷治疗一样有效。重要的是，当与铂类和依托泊苷联合使用时，fimepinostat实现了显著的生存增加。MYC是SCLC中铂类耐药的强劲驱动因素，可以有效用fimepinostat治疗。© 2023. The Author(s).

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance.Elevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC.MYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival.MYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.© 2023. The Author(s).