CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer

J Hematol Oncol. 2020 Jul 20;13(1):99. doi: 10.1186/s13045-020-00926-x.

Abstract

Background: The cyclin-dependent kinase 7 (CDK7) subunit of TFIIH regulates RNA polymerase-II-based transcription and promotes tumor progression. However, the mechanisms involved in CDK7-mediated immune evasion are unclear in non-small cell lung cancer (NSCLC).

Methods: RNA silencing and pharmacologic inhibitors were used to evaluate the functions of CDK7/p38α/MYC/PD-L1 axis in cancer cell proliferation and antiPD-1 therapy resistance. Flow cytometry was performed to detect the status of the immune microenvironment after CDK7 inhibition and antiPD-1 therapy in vivo. CD8 depletion antibodies were used to assess the role of CD8+ T cells in combined CDK7 and PD-1 blockade. The associations among CDK7, p38α, MYC, PD-L1, infiltrating T cells, and survival outcomes were validated in two tissue microarrays and public transcriptomic data of NSCLC.

Results: High CDK7 mRNA and protein levels were identified to be associated with poor prognosis in NSCLC. CDK7 silencing and CDK7 inhibitor THZ1 elicited apoptosis and suppressed tumor growth. Moreover, CDK7 ablation specifically suppressed p38α/MYC-associated genes, and THZ1 inhibited MYC transcriptional activity through downregulating p38α. CDK7 inhibition sensitized NSCLC to p38α inhibitor. Further, THZ1 suppressed PD-L1 expression by inhibiting MYC activity. THZ1 boosted antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with antiPD-1 therapy. The CDK7/MYC/PD-L1 signature and infiltrating T cell status collectively stratified NSCLC patients into different risk groups.

Conclusion: These data suggest that the combined CDK7 inhibitor THZ1 and antiPD-1 therapy can be an effective treatment in NSCLC.

Keywords: CDK7; MYC; Non-small cell lung cancer; PD-L1; p38α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / biosynthesis
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / physiology
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / biosynthesis
  • Cyclin-Dependent Kinases / genetics
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imidazoles / pharmacology*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 14 / physiology
  • Molecular Targeted Therapy*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Phenylenediamines / administration & dosage
  • Phenylenediamines / pharmacology
  • Phenylenediamines / therapeutic use*
  • Prognosis
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / physiology
  • Pyridines / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • RNA Interference
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Signal Transduction / drug effects*
  • Tissue Array Analysis
  • Transcriptome
  • Xenograft Model Antitumor Assays

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Imidazoles
  • MYC protein, human
  • Neoplasm Proteins
  • PDCD1 protein, human
  • Phenylenediamines
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-myc
  • Pyridines
  • Pyrimidines
  • RNA, Messenger
  • RNA, Neoplasm
  • THZ1 compound
  • ralimetinib
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase-activating kinase
  • Mitogen-Activated Protein Kinase 14