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

Ann Thorac Surg. 2022 Nov;114(5):1842-1852. doi: 10.1016/j.athoracsur.2021.08.054. Epub 2021 Sep 27.

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-/- AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth compared with anti-PD-1 or CDK4/6 inhibitor alone.

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.

MeSH terms

  • Animals
  • Apoptosis
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Mesothelioma* / drug therapy
  • Mesothelioma* / genetics
  • Mesothelioma* / metabolism
  • Mesothelioma, Malignant*
  • Mice
  • Nivolumab
  • Pleural Neoplasms* / drug therapy
  • Pleural Neoplasms* / genetics
  • Pleural Neoplasms* / pathology

Substances

  • Cyclin-Dependent Kinase 4
  • Nivolumab
  • Cyclin-Dependent Kinase Inhibitor p16