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Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors
Theresa Baker1, Sujata Nerle1, Justin Pritchard1
1ARIAD Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Abstract:
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.
Insights
Acquired resistance to EZH2 inhibitors (EZH2i) in cancer can arise from specific EZH2 mutations. These mutations, particularly in the D1 domain, confer drug resistance but may be targetable by next-generation EZH2 inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Targeted therapies, including EZH2 inhibitors (EZH2i), offer new cancer treatment avenues.
- Acquired resistance to EZH2i is a significant clinical hurdle.
- Early clinical efficacy of EZH2i like EPZ-6438 and GSK126 has been observed.
Purpose of the Study:
- To identify mechanisms of acquired resistance to EZH2 inhibitors.
- To investigate the role of specific EZH2 mutations in conferring drug resistance.
- To explore the potential for targeting resistant mutations with future therapies.
Main Methods:
- Utilized a forward genetic platform with mutagenesis screening and next-generation sequencing.
- Identified secondary mutations in the EZH2 D1 domain (Y111, I109).
- Assessed the impact of specific mutations (Y111D, A677G, Y641F) on EZH2 inhibitor resistance.
Main Results:
- A hotspot of resistance mutations was identified in the EZH2 D1 domain.
- The Y111D mutation conferred robust resistance to EPZ-6438 and GSK126 across different EZH2 alleles.
- Mutant EZH2 resistance requires histone methyltransferase activity and PRC2 components, and mutations abrogate drug binding.
Conclusions:
- Specific EZH2 D1 domain mutations are key drivers of acquired resistance to EZH2 inhibitors.
- These resistance mechanisms involve the catalytic activity of EZH2 and its interaction with PRC2 components.
- Acquired resistance mutations in both wild-type and mutant EZH2 patients may be targetable by next-generation EZH2 inhibitors.
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