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.

尽管癌症治疗新药的引入取得了快速进展，但耐药性的频繁出现导致疾病进展或肿瘤复发，导致预后不佳。鉴于基因突变被认为是抗癌耐药性的重要驱动因素，因此至关重要的是要确定介导耐药性的突变基因并阐明潜在的分子机制，以开发新的方式来克服化学耐药性并实现更多有效和持久的癌症疗法。累积证据表明，表观遗传改变，尤其是由癌症患者中具有高突变率的表观遗传酶介导的改变，可能是化学抗性发展的关键因素。突变的表观遗传酶改变了酶活性，这可能直接或间接影响组蛋白修饰的水平。这可以改变染色质的结构和功能，从而改变靶基因的表达并最终导致化学抗性。

在当前的综述中，我们总结了表观遗传酶突变及其在临床前耐药模型和复发癌症患者标本中的耐药机制。我们还在 DOT1L 的 DOT1 域中引入了以前未报道的突变位点，这些位点与肺癌耐药性有关。值得注意的是，突变不仅发生在具有酶活性的区域，而且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。这可能为针对表观遗传酶的各种功能域的小分子抑制剂的潜在开发提供基本原理。最后，基于多种耐药机制，我们提出了几种治疗策略来逆转或克服耐药表型，