Reference Detail

Ref Type

Journal Article

PMID

(38833522)

Authors

Keller PJ, Adams EJ, Wu R, Côté A, Arora S, Cantone N, Meyer R, Mertz JA, Gehling V, Cui J, Stuckey JI, Khanna A, Zhao F, Chen Z, Yu Z, Cummings R, Taimi M, Lakhani NJ, Rasco DW, Gutierrez M, Duska L, Devitt M, Rippley R, Levell J, Truong J, Wang J, Sun K, Trojer P

Title

Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research			2024 Jun 04		Cancer Res

URL

Abstract Text

Recurrent somatic mutations in the BAF chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial carcinoma, endometrial cancers, and ovarian clear cell carcinoma, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has previously been identified as targetable vulnerability in the context of ARID1A mutations. Here, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor and elucidate its therapeutic potential for treating ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 cancer patients correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, this data suggests that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents and may be beneficial in various indications with recurrent ARID1A mutations.

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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
ARID1A	S2256*	nonsense	unknown	ARID1A S2256* results in a premature truncation of the Arid1a protein at amino acid 2256 of 2285 (UniProt.org). S2256* has been identified in the scientific literature (PMID: 38833522), but has not been biochemically characterized and therefore, its effect on Arid1a protein function is unknown (PubMed, Jul 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ARID1A inact mut	urinary bladder cancer	sensitive	Tulmimetostat	Preclinical - Pdx	Actionable	In a preclinical study, Tulmimetostat inhibited tumor growth in a bladder cancer patient-derived xenograft (PDX) model harboring a loss of function mutation in ARID1A (PMID: 38833522).	38833522
ARID1A S552*	urinary bladder cancer	sensitive	Tulmimetostat	Preclinical - Cell culture	Actionable	In a preclinical study, Tulmimetostat inhibited viability in 5/6 bladder cancer cell lines harboring ARID1A loss of function mutations including ARID1A S552* in culture (PMID: 38833522).	38833522
ARID1A G1450fs	urinary bladder cancer	sensitive	Tulmimetostat	Preclinical - Cell culture	Actionable	In a preclinical study, Tulmimetostat inhibited viability in 5/6 bladder cancer cell lines harboring ARID1A loss of function mutations including ARID1A G1450fs in culture (PMID: 38833522).	38833522
ARID1A inact mut	endometrial cancer	sensitive	Tulmimetostat	Preclinical - Pdx	Actionable	In a preclinical study, Tulmimetostat inhibited tumor growth in endometrial cancer patient-derived xenograft (PDX) models harboring loss of function mutations in ARID1A (PMID: 38833522).	38833522
ARID1A P549fs ARID1A N756fs	ovarian clear cell carcinoma	sensitive	Tulmimetostat	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Tulmimetostat inhibited viability of an ovarian clear cell carcinoma cell line harboring ARID1A N756fs and P549fs in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38833522).	38833522
ARID1A S2256*	urinary bladder cancer	sensitive	Tulmimetostat	Preclinical - Cell culture	Actionable	In a preclinical study, Tulmimetostat inhibited viability in 5/6 bladder cancer cell lines harboring ARID1A loss of function mutations including ARID1A S2256* in culture (PMID: 38833522).	38833522