CDKN2A/B homozygous deletion sensitizes IDH-mutant glioma to CDK4/6 inhibition.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Ali M Nasser, Lisa Melamed, Ethan Wetzel, Chia-Chen Chang, Hiroaki Nagashima, Yosuke Kitagawa, Logan Muzyka, Hiroaki Wakimoto, Daniel P Cahill, Julie J Miller

TLDR

  • The study looked at how blocking a specific pathway in the body called the CDK-Rb pathway can help treat a type of brain tumor called IDH-mutant gliomas. The researchers used two different drugs called CDKis to block this pathway and found that it helped slow down the growth of the tumors in both lab tests and in mice. They also found that blocking this pathway made the tumors more sensitive to another type of drug called CDK4/6 inhibitors, which improved the survival of the mice with the tumors. The study suggests that CDK4/6 inhibitors could be used to treat IDH-mutant gliomas with deletion of CDKN2A/B in a clinical setting.

Abstract

Treatment paradigms for Isocitrate dehydrogenase (IDH) mutant gliomas are rapidly evolving. While typically indolent and responsive to initial treatment, these tumors invariably recur at 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 outcome. 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 CDKis, 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 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 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 investigation of the use of these agents in a clinical setting.

Overview

  • The study investigates the effect of CDK-Rb pathway blockade on Isocitrate dehydrogenase (IDH) mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi).
  • The study uses cell viability, proliferation assays, and flow cytometry to examine the pharmacologic effect of two distinct CDKis, 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 efficacy and tolerability of CDKi in vivo.

Comparative Analysis & Findings

  • CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in 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.

Implications and Future Directions

  • The study supports investigation of the use of CDK4/6 inhibitors in a clinical setting for IDH-mutant gliomas with deletion of CDKN2A/B. Future research should focus on identifying other potential targets for CDK-Rb pathway blockade in IDH-mutant gliomas and developing more effective and targeted therapies.
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