非小细胞肺癌 (NSCLC) 患者通常年龄较大或身体状况不佳，因此无法耐受标准的积极治疗方案。在我们的研究中，我们测试了 DNA 低甲基化剂地西他滨 (DAC) 与全反式视黄酸 (ATRA) 联合使用的功效，该药物已被证明几乎没有全身副作用。对 56 种 NSCLC 细胞系的广泛筛查发现，联合治疗后 77% 的细胞系细胞活力下降。转录组学、蛋白质组学、增殖和迁移分析表明，快速增殖和缓慢迁移的细胞系对药物组合更敏感。突变谱的比较发现致癌 KRAS 突变仅存在于敏感细胞中。此外，不同的细胞系对治疗表现出异质的基因表达反应，表明不同的作用机制。沉默 KRAS、RIG-I 或 RARB 可部分逆转 KRAS 突变 NCI-H460 细胞的敏感性。为了研究耐药性，我们生成了两个对 ATRA 和 DAC 具有耐药性的 NCI-H460 细胞群，它们比亲本敏感细胞迁移更快，增殖更慢，并显示出衰老迹象。总之，这个综合数据集揭示了 NSCLC 细胞对 DAC 和 ATRA 组合治疗的广泛敏感性，并表明迁移和增殖能力与 NSCLC 药物敏感性相关，因此可以作为 NSCLC 药物敏感性的决定因素。© 2023 作者。约翰·威利出版的《国际癌症杂志》

Non-small cell lung cancer (NSCLC) patients are often elderly or unfit and thus cannot tolerate standard aggressive therapy regimes. In our study, we test the efficacy of the DNA-hypomethylating agent decitabine (DAC) in combination with all-trans retinoic acid (ATRA), which has been shown to possess little systemic adverse effects. Screening a broad panel of 56 NSCLC cell lines uncovered a decrease in cell viability after the combination treatment in 77% of the cell lines. Transcriptomics, proteomics, proliferation and migration profiling revealed that fast proliferating and slowly migrating cell lines were more sensitive to the drug combination. The comparison of mutational profiles found oncogenic KRAS mutations only in sensitive cells. Additionally, different cell lines showed a heterogeneous gene expression response to the treatment pointing to diverse mechanisms of action. Silencing KRAS, RIG-I or RARB partially reversed the sensitivity of KRAS-mutant NCI-H460 cells. To study resistance, we generated two NCI-H460 cell populations resistant to ATRA and DAC, which migrated faster and proliferated slower than the parental sensitive cells and showed signs of senescence. In summary, this comprehensive dataset uncovers a broad sensitivity of NSCLC cells to the combinatorial treatment with DAC and ATRA and indicates that migration and proliferation capacities correlate with and could thus serve as determinants for drug sensitivity in NSCLC.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.