Chen Sihong, Zhao Yingxi, Liu Shougeng, Zhang Jiayu, Assaraf Yehuda G, Cui Wei, Wang Lihui
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.
The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
Drug Resist Updat. 2022 Mar;61:100821. doi: 10.1016/j.drup.2022.100821. Epub 2022 Feb 18.
Despite the rapid advancement in the introduction of new drugs for cancer therapy, the frequent emergence of drug resistance leads to disease progression or tumor recurrence resulting in dismal prognosis. Given that genetic mutations are thought to be important drivers of anti-cancer drug resistance, it is of paramount importance to pin-point mutant genes that mediate drug resistance and elucidate the underlying molecular mechanisms in order to develop novel modalities to surmount chemoresistance and achieve more efficacious and durable cancer therapies. Cumulative evidence suggests that epigenetic alterations, especially those mediated by epigenetic enzymes with high mutation rates in cancer patients, can be a crucial factor in the development of chemoresistance. Mutant epigenetic enzymes have altered enzymatic activity which may directly or indirectly affect the level of histone modifications. This can change chromatin structure and function hence altering the expression of target genes and eventually lead to chemoresistance. In the current review, we summarize epigenetic enzyme mutations and the consequent mechanisms of drug resistance in pre-clinical drug-resistance models and relapsed cancer patient specimens. We also introduce previously unreported mutation sites in the DOT1 domain of DOT1L, which are related to lung cancer drug resistance. It is worth noting that mutations occur not only in domains with enzymatic activity but also in non-catalytic regions. Each protein domain is an evolutionarily conserved region with independent functional properties. This may provide a rationale for the potential development of small molecule inhibitors which target various functional domains of epigenetic enzymes. Finally, based on the multitude of mechanisms of drug resistance, we propose several therapeutic strategies to reverse or overcome drug-resistance phenotypes, with the aim to provide cancer patients with novel efficacious combination therapeutic regimens and strategies to improve patient prognosis.
尽管在引入用于癌症治疗的新药方面取得了快速进展，但耐药性的频繁出现导致疾病进展或肿瘤复发，预后不佳。鉴于基因突变被认为是抗癌耐药性的重要驱动因素，确定介导耐药性的突变基因并阐明其潜在分子机制，对于开发克服化疗耐药性的新方法并实现更有效和持久的癌症治疗至关重要。越来越多的证据表明，表观遗传改变，尤其是那些由癌症患者中高突变率的表观遗传酶介导的改变，可能是化疗耐药性发展的关键因素。突变的表观遗传酶具有改变的酶活性，这可能直接或间接影响组蛋白修饰的水平。这会改变染色质结构和功能，从而改变靶基因的表达，最终导致化疗耐药性。在本综述中，我们总结了临床前耐药模型和复发癌症患者标本中的表观遗传酶突变及其导致的耐药机制。我们还介绍了DOT1L的DOT1结构域中以前未报道的与肺癌耐药性相关的突变位点。值得注意的是，突变不仅发生在具有酶活性的结构域中，也发生在非催化区域。每个蛋白质结构域都是具有独立功能特性的进化保守区域。这可能为靶向表观遗传酶各种功能结构域的小分子抑制剂的潜在开发提供理论依据。最后，基于多种耐药机制，我们提出了几种逆转或克服耐药表型的治疗策略，旨在为癌症患者提供新的有效联合治疗方案和策略，以改善患者预后。
