Reference Detail

Ref Type

Journal Article

PMID

(34027408)

Authors

Sule A, Van Doorn J, Sundaram RK, Ganesa S, Vasquez JC, Bindra RS

Title

Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
NAR cancer	3	2	2021 Jun	zcab018	NAR Cancer

URL

Abstract Text

Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, α-ketoglutarate (αKG), to the oncometabolite 2-hydroxyglutarate (2HG). Our group recently demonstrated that 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state referred to as 'BRCAness', which confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we sought to elucidate sensitivity of IDH1/2-mutant cells to DNA damage response (DDR) inhibitors and, whether combination therapies could enhance described synthetic lethal interactions. Here, we report that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1/2-mutant cells, and that this activity is further potentiated in combination with PARP inhibitors. We demonstrate this interaction across multiple cell line models with engineered and endogenous IDH1/2 mutations, with robust anti-tumor activity in vitro and in vivo. Mechanistically, we found ATR and PARP inhibitor treatment induces premature mitotic entry, which is significantly elevated in the setting of IDH1/2-mutations. These data highlight the potential efficacy of targeting HR defects in IDH1/2-mutant cancers and support the development of this combination in future clinical trials.

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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
IDH1 R132H	Advanced Solid Tumor	sensitive	Ceralasertib + Olaparib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Ceralasertib (AZD6738) resulted in a greater decrease in cell survival compared to Ceralasterib (AZD6738) alone in cells expressing IDH1 R132H in culture, and a longer delay in tumor growth in cell line xenograft models (PMID: 34027408).	34027408
IDH1 R132S	cholangiocarcinoma	sensitive	Ceralasertib + Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Ceralasertib (AZD6738) resulted in a greater decrease in cell viability compared to Ceralasertib (AZD6738) alone in cholangiocarcinoma cells harboring IDH1 R132S in culture (PMID: 34027408).	34027408
IDH1 R132H	Advanced Solid Tumor	sensitive	Elimusertib + Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Elimusertib (BAY1895344) resulted in a greater decrease in cell survival compared to BAY1895344 alone in cells expressing IDH1 R132H in culture (PMID: 34027408).	34027408
IDH1 R132H	Advanced Solid Tumor	sensitive	Elimusertib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with Elimusertib (BAY1895344) resulted in decreased survival in cell lines expressing IDH1 R132H in culture (PMID: 34027408).	34027408
IDH1 R132H	Advanced Solid Tumor	sensitive	Ceralasertib + Niraparib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Zejula (niraparib) and Ceralasertib (AZD6738) resulted in a greater decrease in cell viability compared to Ceralasertib (AZD6738) alone in cells expressing IDH1 R132H in culture (PMID: 34027408).	34027408
IDH1 R132H	Advanced Solid Tumor	sensitive	Ceralasertib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with Ceralasertib (AZD6738) resulted in decreased survival in cell lines expressing IDH1 R132H in culture (PMID: 34027408).	34027408
IDH1 R132H	Advanced Solid Tumor	sensitive	Ceralasertib + Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Talzenna (talazoparib) and Ceralasertib (AZD6738) resulted in a greater decrease in cell viability compared to Ceralasertib (AZD6738) alone in cells expressing IDH1 R132H in culture (PMID: 34027408).	34027408
IDH2 R172S	chondrosarcoma	sensitive	Ceralasertib + Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Ceralasertib (AZD6738) resulted in a greater decrease in cell viability compared to Ceralasertib (AZD6738) alone in chondrosarcoma cells harboring IDH2 R172S in culture (PMID: 34027408).	34027408
IDH1 R132C	fibrosarcoma	sensitive	Ceralasertib + Olaparib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Lynparza (olaparib) and Ceralasertib (AZD6738) resulted in a greater delay in tumor growth compared to Ceralasertib (AZD6738) alone in fibrosarcoma cell line xenograft models harboring IDH1 R132C (PMID: 34027408).	34027408