Effect of CCS1477 treatment on gene expression in NRF2-activated lung cancer cells

Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in KEAP1 mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2’s cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/ p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/ p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation. RNA-Seq profiling of NRF2-activated lung cancer cells H460, H2023 and wildtype lung cancer cell ABC-1 at 24 hours treatment by 5 mM CCS1477

核因子红细胞2相关因子2（NRF2）的组成型激活，通过劫持依赖NRF2的细胞保护性转录程序，为恶性肿瘤克隆提供了选择性生存优势：这一机制可使癌细胞在具有化学应激压力的肿瘤微环境中存活并增殖，同时由于异源生物代谢酶与药物外排泵的上调，还能赋予癌细胞对抗癌药物的耐药性。本研究在KEAP1突变型肺癌细胞中开展小分子表观遗传筛选，鉴定出CCS1477（Inobrodib）是全局性依赖NRF2的转录程序的抑制剂。从机制层面来看，CCS1477可通过抑制NRF2必需的转录激活伴侣CBP/p300，阻遏NRF2的细胞保护性应答。值得注意的是，除了抑制依赖NRF2的抗氧化应激与异源生物代谢酶基因表达外，CCS1477治疗还能够逆转肿瘤细胞的化疗耐药表型，使NRF2激活的肿瘤细胞重新对化疗药物产生敏感性。此外，在KEAP1突变型癌细胞与原代人T细胞的共培养实验中，CCS1477处理可抑制T细胞耗竭转录状态的形成，这将有助于增强抗癌免疫应答。综上，通过抑制CBP/p300发挥作用的CCS1477，为治疗目前尚无有效疗法的NRF2异常激活型肿瘤提供了一种全新的治疗策略。本数据集涵盖经5 mM浓度的CCS1477处理24小时后的NRF2激活型肺癌细胞H460、H2023与野生型肺癌细胞ABC-1的RNA-Seq转录组谱。