Reference Detail

Ref Type

Journal Article

PMID

(38718141)

Authors

Nasser AM, Melamed L, Wetzel EA, Chang JC, Nagashima H, Kitagawa Y, Muzyka L, Wakimoto H, Cahill DP, Miller JJ

Title

CDKN2A/B Homozygous Deletion Sensitizes IDH-Mutant Glioma to CDK4/6 Inhibition.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	30	14	2024 Jul 15	2996-3005	Clin Cancer Res

URL

Abstract Text

Treatment paradigms for isocitrate dehydrogenase (IDH)-mutant gliomas are rapidly evolving. Although typically indolent and responsive to initial treatment, these tumors invariably recur at a higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcomes. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi).Cell viability, proliferation assays, and flow cytometry were used to examine the pharmacologic effect of two distinct CDKi, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant glioma lines. Isogenic models were used to directly investigate the influence of CDKN2A/B status on CDKi sensitivity. Orthotopic xenograft tumor models were used to examine the efficacy and tolerability of CDKi in vivo.CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in the G1 phase. CDKN2A inactivation sensitizes IDH-mutant glioma to CDKi in both endogenous and isogenic models with engineered CDKN2A deletion. CDK4/6 inhibitor administration improves survival in orthotopically implanted IDH-mutant glioma models.IDH-mutant gliomas with deletion of CDKN2A/B are sensitized to CDK4/6 inhibitors. These results support the investigation of the use of these agents in a clinical setting.

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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
CDKN2A del	high grade glioma	sensitive	Abemaciclib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Verzenio (abemaciclib) inhibited viability and G1/S transition in glioma cell lines harboring IDH1 R132H and deletion of CDKN2A in culture and inhibited tumor growth and improved survival in cell line xenograft models (PMID: 38718141).	38718141
CDKN2A del	high grade glioma	sensitive	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, Ibrance (palbociclib) inhibited viability in glioma cell lines harboring IDH1 R132H and deletion of CDKN2A in culture (PMID: 38718141).	38718141