Reference Detail

Ref Type

Journal Article

PMID

(38315003)

Authors

Kazansky Y, Cameron D, Mueller HS, Demarest P, Zaffaroni N, Arrighetti N, Zuco V, Kuwahara Y, Somwar R, Ladanyi M, Qu R, de Stanchina E, Dela Cruz FS, Kung AL, Gounder MM, Kentsis A

Title

Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery			2024 Feb 05		Cancer Discov

URL

Abstract Text

Epigenetic dependencies have become evident in many cancers. Based on antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we recently completed the clinical trial of the EZH2 inhibitor tazemetostat. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics and diverse experimental models, we define molecular mechanisms of tazemetostat resistance in SMARCB1-deficient tumors. We found distinct acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest, suggests a general mechanism for effective therapy, and provides prospective biomarkers for therapy stratification, including PRICKLE1. Based on this, we develop a combination strategy to circumvent tazemetostat resistance using bypass targeting of AURKB. This offers a paradigm for rational epigenetic combination therapy suitable for translation to clinical trials for epithelioid sarcomas, rhabdoid tumors, and other epigenetically dysregulated cancers.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RB1 del SMARCB1 loss	rhabdoid cancer	sensitive	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, Roscovotine (seliciclib) inhibited viability of a SMARCB1-deficient rhabdoid cancer cell line with a deletion of RB1 in culture (PMID: 38315003).	38315003
SMARCB1 loss	epithelioid sarcoma	sensitive	Barasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Barasertib (AZD1152) inhibited viability of SMARCB1-deficient epithelioid sarcoma cell lines in culture (PMID: 38315003).	38315003
SMARCB1 loss	rhabdoid cancer	sensitive	Barasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Barasertib (AZD1152) inhibited viability of SMARCB1-deficient rhabdoid cancer cell lines in culture (PMID: 38315003).	38315003
RB1 del SMARCB1 loss	rhabdoid cancer	sensitive	Barasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Barasertib (AZD1152) inhibited viability of a SMARCB1-deficient rhabdoid cancer cell line with a deletion of RB1 in culture (PMID: 38315003).	38315003
RB1 I124Rfs*6 RB1 del SMARCB1 loss	epithelioid sarcoma	predicted - resistant	Tazemetostat	Case Reports/Case Series	Actionable	In a clinical case study, a patient with SMARCB1-deficient epithelioid sarcoma progressed on treatment with Tazverik (tazemetostat) and was found to have acquired a hemizygous deletion of RB1 and RB1 I124Rfs*6 (PMID: 38315003).	38315003
RB1 del SMARCB1 loss	rhabdoid cancer	sensitive	Alisertib	Preclinical - Cell culture	Actionable	In a preclinical study, Alisertib (MLN8237) inhibited viability of a SMARCB1-deficient rhabdoid cancer cell line with a deletion of RB1 in culture (PMID: 38315003).	38315003
RB1 del SMARCB1 loss	rhabdoid cancer	resistant	Tazemetostat	Preclinical - Cell culture	Actionable	In a preclinical study, a SMARCB1-deficient rhabdoid cancer cell line with a deletion of RB1 was resistant to Tazverik (tazemetostat) in culture (PMID: 38315003).	38315003