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Investigating Resistance to EZH2 Inhibition in ARID1A-Mutated Ovarian Cancer Cells

By: Kayci Reyer
Posted: Wednesday, November 14, 2018

A driving factor in resistance to EZH2 inhibition in ARID1A-mutated ovarian cancer cells seems to be a switch between SWI/SNF (mating type switching/sucrose nonfermenting) catalytic subunits, according to a study published in Nature Communications. Specifically, the resistance is caused by a subunit switch from SMARCA4 to SMARCA2.

Rugang Zhang, PhD, of The Wistar Institute in Philadelphia, and colleagues developed EZH2-resistant ARID1A-mutated clones using continuous gradual exposure to GSK126, a highly selective EZHS methyltransferase inhibitor. These clones displayed resistance to multiple EZH2 inhibitors.

The authors noted, “The observed resistance was not due to the inability of the EZH2 inhibitor to suppress EZH2 enzymatic activity because H3K27Me3, the enzymatic product of EZH26, remained ablated in [EZH2 inhibitor–resistant] cells. There is evidence to suggest that a decrease in stabilization of the [polycomb repressive complex 2] contributes to intrinsic resistance to EZH2 inhibitors in SWI/SNF-mutated cells. However, the interaction between EZH2 and SUZ12 was not decreased in the [EZH2 inhibitor–resistant] cells, suggesting that the observed resistance was not due to a decrease in [polycomb repressive complex 2] stability.”

Based on that finding, researchers sought to narrow down the driver of the clones’ resistance by immunoprecipitating subunit SMARCC1 to isolate the SWI/SNF complex. Mass spectrometry and stoichiometry analysis showed a subunit switch from SMARCA4 to SMARCA2. The loss of SMARCA4 was noted to upregulate antiapoptotic genes in the resistant cells. In addition, ARID1A-mutated cells were found to be sensitive to BCL2 inhibitors such as ABT-263 (navitoclax), which is capable of overcoming EZH2 resistance.

“BCL2 inhibition alone or in combination with EZH2 inhibition represents [an] urgently needed therapeutic strategy for ARID1A-mutated cancers,” the investigators concluded.

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