BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras-Mutant Non-Small Cell Lung Cancer.

Abstract

KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances in targeted therapy have shown great promise, effective targeting of KRAS remains elusive, and concurrent alterations in tumor suppressors render KRAS-mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS-mutant tumors are immunosuppressive mechanisms, such as increased presence of suppressive regulatory T cells (Treg) in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells. Treatment with BET bromodomain inhibitors is beneficial for hematologic malignancies, and they have Treg-disruptive effects in a non-small cell lung cancer (NSCLC) model. Targeting PD-1-inhibitory signals through PD-1 antibody blockade also has substantial therapeutic impact in lung cancer, although these outcomes are limited to a minority of patients. We hypothesized that the BET bromodomain inhibitor JQ1 would synergize with PD-1 blockade to promote a robust antitumor response in lung cancer. In the present study, using Kras+/LSL-G12D ; Trp53L/L (KP) mouse models of NSCLC, we identified cooperative effects between JQ1 and PD-1 antibody. The numbers of tumor-infiltrating Tregs were reduced and activation of tumor-infiltrating T cells, which had a T-helper type 1 (Th1) cytokine profile, was enhanced, underlying their improved effector function. Furthermore, lung tumor-bearing mice treated with this combination showed robust and long-lasting antitumor responses compared with either agent alone, culminating in substantial improvement in the overall survival of treated mice. Thus, combining BET bromodomain inhibition with immune checkpoint blockade offers a promising therapeutic approach for solid malignancies such as lung adenocarcinoma. Cancer Immunol Res; 6(10); 1234-45. ©2018 AACR.

• Authors: Dennis O Adeegbe, Shengwu Liu, Maureen M Hattersley, Michaela Bowden, Chensheng W Zhou, Shuai Li, Raven Vlahos, Michael Grondine, Igor Dolgalev, Elena V Ivanova, Max M Quinn, Peng Gao, Peter S Hammerman, James E Bradner, J Alan Diehl, Anil K Rustgi, Adam J Bass, Aristotelis Tsirigos, Gordon J Freeman, Huawei Chen, Kwok-Kin Wong
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 6 Issue 10 Pg. 1234-1245 (10 2018) ISSN: 2326-6074 [Electronic] United States
• PMID: 30087114 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• (+)-JQ1 compound
• Azepines
• Cytokines
• Nuclear Proteins
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Triazoles
• Trp53 protein, mouse
• Tumor Suppressor Protein p53
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Adoptive Transfer
• Animals
• Azepines (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, immunology)
• Cytokines (immunology)
• Lung Neoplasms (drug therapy, immunology)
• Mice, Nude
• Mice, Transgenic
• Mutation
• Nuclear Proteins (antagonists & inhibitors)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Proto-Oncogene Proteins p21(ras) (genetics)
• T-Lymphocytes (immunology)
• Triazoles (therapeutic use)
• Tumor Suppressor Protein p53 (deficiency)