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

• DOI: 10.1186/s13045-020-00926-x
• Publication Date: 2020-07-20T10:04:26Z
• Authors: Jian Wang; Ruiguang Zhang; Zhenyu Lin; Sheng Zhang; Yaobing Chen; Jing Tang; Jiaxin Hong; Xiaoshu Zhou; Yan Zong; Yingzhuo Xu; Rui Meng; Shuangbing Xu; Li Liu; Tao Zhang; Kunyu Yang; Xiaorong Dong; Gang Wu
• Keywords: p38α; PD-L1; 0301 basic medicine; Lung Neoplasms; CDK7; Mice, Nude; MYC; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Mitogen-Activated Protein Kinase 14; Mice; 03 medical and health sciences; Lymphocytes, Tumor-Infiltrating; Non-small cell lung cancer; Carcinoma, Non-Small-Cell Lung; Animals; Humans; Diseases of the blood and blood-forming organs; Molecular Targeted Therapy; RC254-282; Mice, Inbred BALB C; Research; Imidazoles; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Drug Synergism; Cyclin-Dependent Kinases; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Drug Resistance, Neoplasm; Female; RC633-647.5

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.