Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas

Abstract

Resistance to targeted therapies has become increasingly prevalent. We noted that resistance to different targeted therapies occurs by largely common mechanisms. 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 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. Constitutive activation of IGF-1R, MEK, or PI3K pathways was sufficient to confer resistance to EZH2 inhibitors in DLBCL. 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. We also identified multiple acquired mutations in EZH2 inhibitor-resistant DLBCL cell lines. These mutations independently conferred resistance to EZH2 inhibitors. 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. 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. 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.

Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

“…Crosstalk between epigenetic modulators and signaling pathways has already been reported in some contexts . Bisserier and Wajapeyee (2018) found that resistance to EZH2 inhibition in lymphoma cells may be acquired through the activation of the PI3K/Akt pathway, and the inhibition of PI3K sensitized resistant cancer cells to the cytotoxic effects of EZH2 inhibitors . Based on these findings, we treated myeloma cell lines with TAS‐117 in combination with either the dual EZH2/EZH1 inhibitor, UNC1999 (IC50, EZH2 < 10 nmol/L; EZH1 45 nmol/L), or a selective EZH2 inhibitor, GSK126 (IC50, EZH2 9.9 nmol/L; EZH1 680 nmol/L) .…”

Epigenetic inhibitors sensitize DLBCL cells to rituximab and doxorubicin

“…We detected likely pathogenic mutations in doxorubicin related genes ( 24 ) including TP53 , AKT1 , and EZH2 , and targets of vorinostat TP53 , EZH2 and MYD88 (VAF=1 indicates loss of heterozygosity). Tazemetostat also acts through inhibition of EZH2 , and the specific missense mutation p.Y590S found in Su-Dhl-4 (the tazemetostat responsive cell line) has been reported to increase sensitivity to EZH2 inhibitors ( 25 ). Notably, the majority of these genes are among the most recurrently altered drivers in DLBCL ( MYD88 in 18%, CREBBP , ARLD1A , and TP53 in 10%, and EZH2 in 6% of patients) ( 26 ).…”

Germinal center‐derived lymphomas: The darkest side of humoral immunity

“…Important considerations with these agents include that (a) sustained target suppression is probably important, and may be difficult to achieve especially in more aggressive tumors, (b) aside from EZH2 mutation, there is no biomarker to predict which EZH2 wildtype patients might respond, and (c) these drugs are mostly cytostatic, so that combination with other agents is needed to achieve maximal effect. 188 It will be necessary to follow the outcomes of clinical trials with different EZH2 inhibitors of varying potency, mechanism of action and pharmacokinetics to fully understand the optimal manner in which to use this modality in the clinic. 16 Given the role of mutant EZH2 in suppressing MHC I/II, it seems likely that these drugs would greatly enhance the efficacy of immunotherapies such as checkpoint inhibitors.…”

“…114 Although current regimens involve continuous and prolonged dosing, this can lead to the development of resistance and may not be necessary if the drug is used in more brief cycles in combination. 188 It will be necessary to follow the outcomes of clinical trials with different EZH2 inhibitors of varying potency, mechanism of action and pharmacokinetics to fully understand the optimal manner in which to use this modality in the clinic.…”