Program in Solid Tumors, Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Pamplona, Spain.
CIBERONC, ISCIII, Madrid, Spain.
Cell Death Dis. 2024 Nov 2;15(11):787. doi: 10.1038/s41419-024-07156-w.
The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer. We observed co-expression and overexpression of G9a and DNMT1 in NSCLC, which were associated with poor prognosis. Co-targeting G9a/DNMT1 with the drug CM-272 reduced proliferation and induced cell death in a panel of human and murine NSCLC cell lines. Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). In vivo, CM-272 reduced tumor volume in human and murine cell-derived cancer models, and this effect was synergistically enhanced by cisplatin. The expression of SCARA5 and AOX1 was induced by CM-272, and both proteins were found to be essential for the antiproliferative response, as gene silencing decreased cytotoxicity. Furthermore, the expression of SCARA5 and AOX1 was positively correlated with each other and inversely correlated with G9a and DNMT1 expression in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.
治疗非小细胞肺癌 (NSCLC) 患者的方法随着最近治疗策略的发展已经显著改善；然而，许多患者仍然不能从中受益。因此，急需新的治疗方法。在这项研究中，我们评估了靶向 G9a 和 DNMT1 酶的联合治疗的抗肿瘤疗效及其作为癌症药物增敏剂的潜力。我们观察到 G9a 和 DNMT1 在 NSCLC 中的共表达和过表达，这与预后不良有关。用药物 CM-272 靶向 G9a/DNMT1 可减少一组人类和鼠类 NSCLC 细胞系的增殖并诱导细胞死亡。此外，这些细胞的转录组被重新编程，使其对化疗（顺铂）、靶向治疗（曲美替尼）和表观遗传治疗（伏立诺他）高度敏感。在体内，CM-272 减少了人源和鼠源细胞衍生的癌症模型中的肿瘤体积，并且这种作用通过顺铂协同增强。CM-272 诱导了 SCARA5 和 AOX1 的表达，并且这两种蛋白质对于抑制增殖反应是必需的，因为基因沉默降低了细胞毒性。此外，SCARA5 和 AOX1 的表达彼此之间呈正相关，与 NSCLC 患者中的 G9a 和 DNMT1 表达呈负相关。SCARA5 和 AOX1 的 DNA 启动子在 NSCLC 中呈高甲基化状态，并且在肿瘤和 NSCLC 患者的液体活检中，SCARA5 甲基化被鉴定为一种表观遗传生物标志物。因此，我们证明靶向 G9a/DNMT1 是增强癌症药物疗效的一种很有前途的策略，并且 SCARA5 甲基化可以作为监测肿瘤进展的非侵入性生物标志物。
