Inhibition of Cyclin Dependent Kinase 4/6 Overcomes Primary Resistance to Programmed Cell Death 1 Blockade in Malignant Mesothelioma

Authors

Hee-Jin Jang
Cynthia Y Truong
Eric M Lo
Hudson M Holmes
Daniela Ramos
Maheshwari Ramineni
Ju-Seog Lee
Daniel Y Wang
Massimo Pietropaolo
R Taylor Ripley
Bryan M Burt
Hyun-Sung Lee

Publication Date

11-1-2022

Journal

The Annals of Thoracic Surgery

Abstract

BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with programmed cell death 1 (PD-1) blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remains unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.

METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 nonresponders). We used The Cancer Genome Atlas MPM cohort (n = 73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model.

RESULTS: Immunogenomic analysis by applying our anti-PD-1 resistance signature to The Cancer Genome Atlas cohort revealed that deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by cyclin dependent kinase 4/6 (CDK4/6) inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a

CONCLUSIONS: We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.

Keywords

Mice, Animals, Mesothelioma, Malignant, Cyclin-Dependent Kinase 4, Nivolumab, Cyclin-Dependent Kinase Inhibitor p16, Mesothelioma, Apoptosis, Pleural Neoplasms

Comments

Supplementary Material

PMID: 34592265

DOI

10.1016/j.athoracsur.2021.08.054

PMID

34592265

PMCID

PMC8957629

PubMedCentral® Posted Date

November 2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes