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Ref Type Journal Article
PMID (26360609)
Authors Baker T, Nerle S, Pritchard J, Zhao B, Rivera VM, Garner A, Gonzalvez F
Title Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors.
Journal Oncotarget
Vol 6
Issue 32
Date 2015 Oct 20
URL
Abstract Text Although targeted therapies have revolutionized cancer treatment, overcoming acquired resistance remains a major clinical challenge. EZH2 inhibitors (EZH2i), EPZ-6438 and GSK126, are currently in the early stages of clinical evaluation and the first encouraging signs of efficacy have recently emerged in the clinic. To anticipate mechanisms of resistance to EZH2i, we used a forward genetic platform combining a mutagenesis screen with next generation sequencing technology and identified a hotspot of secondary mutations in the EZH2 D1 domain (Y111 and I109). Y111D mutation within the WT or A677G EZH2 allele conferred robust resistance to both EPZ-6438 and GSK126, but it only drove a partial resistance within the Y641F allele. EZH2 mutants required histone methyltransferase (HMT) catalytic activity and the polycomb repressive complex 2 (PRC2) components, SUZ12 and EED, to drive drug resistance. Furthermore, D1 domain mutations not only blocked the ability of EZH2i to bind to WT and A677G mutant, but also abrogated drug binding to the Y641F mutant. These data provide the first cellular validation of the mechanistic model underpinning the oncogenic function of WT and mutant EZH2. Importantly, our findings suggest that acquired-resistance to EZH2i may arise in WT and mutant EZH2 patients through a single mutation that remains targetable by second generation EZH2i.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
EZH2 I109K missense unknown EZH2 I109K lies within the D1 domain of the Ezh2 protein (PMID: 26360609). I109K has been demonstrated to occur as a secondary mutation that confers resistance to Ezh2 inhibitors (PMID: 26360609), but has not been biochemically characterized and therefore, its effect on Ezh2 protein function is unknown (PubMed, Apr 2020). Y
EZH2 Y111D missense unknown EZH2 Y111D lies within the D1 domain of the Ezh2 protein (PMID: 26360609). Y111D has been demonstrated as to occur as a secondary mutation that confers resistance to Ezh2 inhibitors (PMID: 30555699, PMID: 26360609), but has not been biochemically characterized and therefore, its effect on Ezh2 protein function is unknown (PubMed, Apr 2020). Y
EZH2 Y111N missense unknown EZH2 Y111N lies within the D1 domain of the Ezh2 protein (PMID: 26360609). Y111N has been demonstrated to occur as a secondary mutation that confers resistance to Ezh2 inhibitors (PMID: 26360609), but has not been biochemically characterized and therefore, its effect on Ezh2 protein function is unknown (PubMed, Apr 2020). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EZH2 Y111D EZH2 A677G Advanced Solid Tumor resistant Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, transformed cells overexpressing EZH2 and carrying simultaneous A677G and Y111D mutations were resistant to Tazemetostat (EPZ-6438) in culture (PMID: 26360609). 26360609
EZH2 Y111D EZH2 Y641F Advanced Solid Tumor decreased response Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing EZH2 carrying simultaneous Y641F and Y111D mutations demonstrated reduced sensitivity to Tazemetostat (EPZ-6438) in culture (PMID: 26360609). 26360609
EZH2 Y111D SMARCB1 inact mut rhabdoid cancer resistant Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, over expression of EZH2 Y111D in rhabdoid tumor cells harboring an SMARCB1 inactivating mutation resulted in resistance to Tazemetostat (EPZ-6438) treatment in culture (PMID: 26360609). 26360609
EZH2 Y111D Advanced Solid Tumor resistant Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, over expression of EZH2 Y111D in transformed cells harboring wild-type Ezh2 resulted in resistance to Tazemetostat (EPZ-6438) treatment in culture (PMID: 26360609). 26360609
EZH2 Y111D EZH2 A677G B-cell lymphoma resistant GSK126 Preclinical - Cell culture Actionable In a preclinical study, EZH2 Y111D conferred resistance to GSK126 when occurred in the same allele as EZH2 A677G in B-cell lymphoma cells in culture (PMID: 26360609). 26360609
EZH2 Y111D EZH2 Y641F Advanced Solid Tumor predicted - resistant GSK126 Preclinical - Cell culture Actionable In a preclinical study, transformed cells overexpressing EZH2 and carrying simultaneous Y641F and Y111D mutations demonstrated reduced sensitivity to GSK126 in culture (PMID: 26360609). 26360609
EZH2 Y111D EZH2 A677G B-cell lymphoma resistant Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, EZH2 Y111D conferred resistance to Tazemetostat (EPZ-6438) when occurring in the same allele as EZH2 A677G in B-cell lymphoma cells in culture (PMID: 26360609). 26360609
EZH2 Y111D Advanced Solid Tumor resistant GSK126 Preclinical - Cell culture Actionable In a preclinical study, over expression of EZH2 Y111D in transformed cells harboring wild-type Ezh2 resulted in resistance to GSK126 treatment in culture (PMID: 26360609). 26360609
EZH2 Y111D EZH2 A677G Advanced Solid Tumor resistant GSK126 Preclinical - Cell culture Actionable In a preclinical study, transformed cells overexpressing EZH2 and carrying simultaneous A677G and Y111D mutations were resistant to GSK126 in culture (PMID: 26360609). 26360609