CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer
Posted on 2020-07-21 - 05:10
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.
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Wang, Jian; Zhang, Ruiguang; Lin, Zhenyu; Zhang, Sheng; Chen, Yaobing; Tang, Jing; et al. (2020). CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.5068476.v1
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AUTHORS (17)
JW
Jian Wang
RZ
Ruiguang Zhang
ZL
Zhenyu Lin
SZ
Sheng Zhang
YC
Yaobing Chen
JT
Jing Tang
JH
Jiaxin Hong
XZ
Xiaoshu Zhou
YZ
Yan Zong
YX
Yingzhuo Xu
RM
Rui Meng
SX
Shuangbing Xu
LL
Li Liu
TZ
Tao Zhang
KY
Kunyu Yang
XD
Xiaorong Dong
GW
Gang Wu