Epigenetic enzyme mutations as mediators of anti-cancer drug resistance

https://doi.org/10.1016/j.drup.2022.100821Get rights and content

Abstract

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.

Introduction

Malignant tumors constitute a serious threat to human health and life (Cao et al., 2020; Siegel et al., 2020). In recent years, while treatment modalities have developed from traditional surgery and chemoradiotherapy to targeted therapy and precision medicine, the inevitable drug resistance remains the primary hindrance to curative cancer therapy (Aleksakhina et al., 2019; Hu and Zhang, 2016). Genomic alterations constitute the most common drivers of cancer progression and anti-cancer drug resistance; these chemoresistance mechanisms include impaired drug uptake, drug efflux, altered drug target, drug sequestration away from the drug target, activation of alternative signaling pathways, epithelial-mesenchymal transition (EMT), and impaired apoptosis (Aleksakhina et al., 2019; Assaraf et al., 2019; Beerenwinkel et al., 2015; Binenbaum et al., 2015; Erin et al., 2020; Gacche and Assaraf, 2018; Li et al., 2016; Martinez-Jimenez et al., 2020; Shahar and Larisch, 2020; Wang et al., 2021; Zhitomirsky and Assaraf, 2016). A mutation in the drug target can alter its structure, reducing or abolishing drug binding, hence rendering it insensitive to the drug. Taking non-small cell lung cancer (NSCLC) as an example, patients with activating mutations in epidermal growth factor receptor (EGFR) often develop resistance to first-generation tyrosine kinase inhibitors (TKIs) via acquisition of the p.T790M mutation (Gillis and McLeod, 2016; Juchum et al., 2015; Leonetti et al., 2019a, b). So far, three generations of drugs have been developed on account of the continuous mutations in the drug target EGFR (Du et al., 2021; Robichaux et al., 2021; Wu and Shih, 2018). Osimertinib, a third-generation EGFR-targeted TKI is mainly aimed at targeting the p.T790M mutation, but unfortunately there is currently no novel EGFR-targeting drug available to replace it when drug resistance mutations inevitably arise (Oxnard et al., 2018). Similarly, a secondary mutation p.G2032R in the ROS proto-oncogene 1 (ROS1) kinase domain can confer resistance to crizotinib in lung adenocarcinoma (Awad et al., 2013). In addition, genomic alterations that dysregulate signal transduction proteins acting either upstream or downstream of drug targets can also confer drug resistance; these include activating mutations in the oncogenes RAS, RAF and PI3K, and inactivating mutations of tumor suppressor genes including TP53, PTEN and RB1 (Cao et al., 2020; Gao et al., 2021; Martincorena and Campbell, 2015; Martinez-Jimenez et al., 2020; Stiewe and Haran, 2018; Zhang et al., 2017). More recently, it has been demonstrated that epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression, invasion and metastasis (Li et al., 2020b; Roy et al., 2014; Wilting and Dannenberg, 2012). Next-generation sequencing (NGS) technologies have identified driver mutations in genes encoding for epigenetic regulators, which provides a mechanistic link between the cancer epigenome and genetic alterations (Andrei et al., 2020; Duy et al., 2019; Jones et al., 2016; Kudithipudi and Jeltsch, 2014; Lafave and Levine, 2013; Lunning and Green, 2015; Wan et al., 2020). For example, gain-of-function (GOF) mutations or loss-of-function (LOF) mutations can occur in EZH2. Both mutation types have the potential to be involved in the occurrence and development of tumors, and further have an adverse effect on drug sensitivity (Gollner et al., 2017; Shen and Vakoc, 2015). Investigations into the role of LOF mutations in KDM6A, CREBBP/EP300 and other proteins implicate these genes as tumor suppressors (Bisserier and Wajapeyee, 2018; Liu et al., 2020; Salgia and Kulkarni, 2018). In our previous work, we have discussed how aberrant mutations and expression of histone methyltransferases and acetyltransferases usually affect tumor-related factors, promote malignant behavior of tumors, and eventually provoke drug resistance (Okugawa et al., 2015; Wang et al., 2020; Wiesel-Motiuk and Assaraf, 2020; Yang et al., 2020). Based on the high mutation rate of epigenetic regulatory enzymes in cancers according to the COSMIC database (Fig. 1) (Roy et al., 2014; Zerbino et al., 2018), we systematically reviewed the relationship between mutations of epigenetic regulatory enzymes and tumorigenesis (Han et al., 2019). However, few reviews have summarized the relationship between epigenetic regulation and anti-cancer drug resistance using epigenetic enzyme mutations as an entry point (Bates, 2020; Helin and Dhanak, 2013).

Recently, John V. Heymach's team at the University of Texas MD Anderson Cancer Center reported that separating EGFR mutations by structure and function predicted drug response in EGFR-mutant NSCLC, providing a more precise framework for matching patients to the appropriate targeted agent (Robichaux et al., 2021). By coincidence, this review outlines multiple epigenetic enzyme mutations associated with anti-cancer drug resistance and classifies these mutations by the domains in which they are located, as shown in Fig. 2. We also discuss the function of the domains containing the mutations, and predict other possible drug resistance mechanisms resulting from mutations in the different domains. This delineation is expected to provide greater insights into the structure and function relationship of epigenetic enzyme mutations on drug sensitivity (Li et al., 2019; Robichaux et al., 2021). Finally, we highlight some of the more recent progress towards strategies to reverse or overcome drug resistance caused by epigenetic enzyme mutations, as depicted in Figs. 3 and 4 . These strategies should provide new avenues for therapeutic interventions in cancer from the perspective of epigenetic regulation.

Section snippets

SET domain mutation

The SET domain (Su(var)3-9, Enhancer of zeste and Trithorax) was first recognized as a conserved feature in a few chromatin-associated proteins and has now been identified in hundreds of other proteins (Wu et al., 2013). Emerging data suggest that proteins bearing the SET domain can methylate lysine residues in histones. Furthermore, gene silencing and chromatin remodeling resulting from change-of-function mutations in the SET domain of histone methyltransferase have been shown to be involved

Targeting mutated epigenetic enzymes and altered downstream genes

Inspired by the above findings, researchers have attempted to develop inhibitors that target mutated epigenetic enzymes to overcome anti-cancer drug resistance, as detailed in Figs. 3A and 4 (Arrowsmith et al., 2012). For instance, diffuse large B-cell lymphoma (DLBCL) cells with EZH2C663Y or EZH2Y726F mutations were resistant to GSK126 and EPZ-6438 by sustaining H3K27me3, but remained sensitive to another EZH2 inhibitor UNC1999 (Bisserier and Wajapeyee, 2018). This means that switching the

Conclusions and perspectives

A new perspective has emerged in the area of cancer therapy with the discovery that mutations in epigenetic enzymes are related to drug resistance in cancer cells (Mohammad et al., 2019). Epigenetic enzymes often contain several functional protein domains each of which may have a distinct role in epigenetic regulation. Hence, it is critical to identify the precise domain responsible for the resistance phenotype to inform rational drug design (Dawson, 2017).

In general, mutations occurring in the

Data availability

Data will be made available on request.

The data that has been used is confidential.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82073320, 81773216, 81773780, 81673652), the “Xingliao Talents” Program of Liaoning Province (No. XLYC1902008), the Youth Science and Technology Innovation Leader Program of Shenyang (No. RC190457) and the Central Guidance on Local Science and Technology Development Fund of Liaoning Province (To Wei Cui).

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