5Įnhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb-repressive complex 2 (PRC2), which functions as a transcriptional repressor, in part, by methylating histone H3 at lysine 27 (H3K27). 3, 4 Collectively, these studies have identified 2 major mechanisms that drive acquired resistance to targeted therapeutic agents: (1) the activation of prosurvival pathways, and (2) secondary mutations in target proteins that prevent drug binding. 3 Due to the clinical significance of the problem, tremendous efforts have been devoted to understanding the mechanisms underlying resistance to specific targeted cancer therapies. 2 Nonetheless, despite the benefits provided by targeted therapies, acquired resistance to targeted therapeutic agents, which renders the therapies ineffective, has emerged in a large majority of cancer patients. 1 However, an improved understanding of cancer landscapes has resulted in the identification of cancer cell-specific vulnerabilities, which has led to the development of cancer-specific targeted therapies. Collectively, our results underpin the importance for developing a unified approach for forestalling drug resistance by prospectively considering lessons learned from the use of different targeted therapeutic agents.įor decades, traditional cytotoxic chemotherapies have been used to treat a wide variety of cancers. Notably, EZH2 inhibitor GSK126- and EPZ-6438–resistant DLBCL cells remained sensitive to the EZH2 inhibitor UNC1999 and embryonic ectoderm development protein inhibitor EED226, which provides an opportunity to treat DLBCLs that are resistant to these drugs. Mechanistically, cellular thermal shift assays revealed that the acquired EZH2 mutations that confer resistance to EZH2 inhibitors prevent EZH2 inhibitor binding to the EZH2 mutants. These mutations independently conferred resistance to EZH2 inhibitors.
We also identified multiple acquired mutations in EZH2 inhibitor-resistant DLBCL cell lines. The activation of the PI3K/AKT and MAPK pathways decreased TNFSF10 and BAD expression through a FOXO3-dependent mechanism, which was required for the antitumor effects of EZH2i GSK126.
Constitutive activation of IGF-1R, MEK, or PI3K pathways was sufficient to confer resistance to EZH2 inhibitors in DLBCL. We discovered that EZH2 inhibitor-resistant DLBCL cells showed activation of the insulin-like growth factor 1 receptor (IGF-1R), MEK, and phosphoinositide-3-kinase (PI3K) pathways. In this study, we used this information for identifying the mechanisms of resistance to enhancer of zeste homolog 2 (EZH2) inhibitors in diffuse large B-cell lymphoma (DLBCL) harboring EZH2 mutations. We noted that resistance to different targeted therapies occurs by largely common mechanisms. Resistance to targeted therapies has become increasingly prevalent.
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