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

Journal of Hematology & Oncology
Jian WangGang Wu

Abstract

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). 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. 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-...Continue Reading

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Citations

Dec 19, 2020·Cancer Cell·Giulia PetroniLorenzo Galluzzi
Jun 6, 2021·Journal of Experimental & Clinical Cancer Research : CR·Hao ZhangQuan Cheng
Jul 6, 2021·European Journal of Pharmacology·Yun Jung ChoiJin Kyung Rho

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Datasets Mentioned

BETA
GSE37745

Methods Mentioned

BETA
RNA-seq
xenograft
FACS
gene
flow cytometry
ELISA

Software Mentioned

GraphPad Prism
R
GEPIA
DAVID
gene set enrichment analysis ( GSEA )
CompuSyn
FlowJo

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