CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer

Zhang, Hua; Christensen, Camilla L.; Dries, Ruben; Oser, Matthew G.; Deng, Jiehui; Diskin, Brian; Li, Fēi; Pan, Yun; Zhang, Xuzhu; Yin, Yandong; Papadopoulos, Eleni; Pyon, Val; Thakurdin, Cassandra; Kwiatkowski, Nicholas; Jani, Kandarp; Rabin, Alexandra R.; Castro, Dayanne M.; Chen, Ting; Silver, Heather; Huang, Qingyuan; Bulatović, Mirna; Dowling, Catríona M.; Sundberg, Belen; Leggett, Alan L.; Ranieri, Michela; Han, Han; Li, Shuai; Yang, Annan; Labbe, Kristen; Almonte, Christina; Sviderskiy, Vladislav O.; Quinn, Max M.; Donaghue, Jack; Wang, Eric S.; Zhang, Tinghu; He, Zhixiang; Velcheti, Vamsidhar; Hammerman, Peter S.; Freeman, Gordon J.; Bonneau, Richard; Kaelin, William G.; Sutherland, Kate D.; Kersbergen, Ariena; Aguirre, Andrew J.; Yuan, Guo Cheng; Rothenberg, Eli; Miller, George; Gray, Nathanael S.; Wong, Kwok-Kin

doi:10.1016/j.ccell.2019.11.003

Cited by 148 publications

(142 citation statements)

References 62 publications

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“…Then, we showed that THZ1 sensitized tumors to antiPD-1 antibodies in vivo by decreasing PD-L1 expression and recruiting infiltrating CD8 + T cells which drive the antitumor immunity response [25]. A recent study showed that CDK7 inhibitor YKL-5-124 causes DNA damage in small cell lung cancer (SCLC) and sensitizes tumors to antiPD-1 therapy by provoking a robust immune surveillance program elicited by T cells [52]. In contrast to THZ1, YKL-5-124 treatment had no effect on CTD phosphorylation of RNA Pol II, indicating that YKL-5-124 does not inhibit global transcription.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Furthermore, the combination of a CHK1 inhibitor and low dose gemcitabine enhanced the effect of PD-L1 inhibition (45), and concomitant treatment with a DDR inhibitor remarkably potentiated the antitumor effects of PD-L1 inhibition in mouse models of SCLC (46). Treatment with a cyclin-dependent kinase 7 inhibitor, YKL-5-124, was also found to enhance anti-tumor efficacy of a PD-1 inhibitor in SCLC preclinical models (47). Several clinical trials using immune checkpoint inhibitor combinations are ongoing (48).…”

Section: Immunotherapy Regimens and Combinations For Sclcmentioning

confidence: 94%

Targeted Therapies and Biomarkers in Small Cell Lung Cancer

2020

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Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid growth, early metastasis, and acquired therapeutic resistance. A majority of patients with SCLC have extensive-stage (ES) disease, defined as the presence of metastatic disease outside the hemithorax at first diagnosis. SCLC has been considered "a graveyard for drug development," with chemotherapy remaining the standard treatment for first-and second-line management until quite recently. In contrast to NSCLC, identifying therapeutic targets in SCLC has been challenging, partly because driver mutations are primarily loss of function, involving the tumor suppressor genes RB1 and TP53 or currently untargetable (e.g., amplification of MYC family members). Recent gene expression profiling of SCLC cells lines, patient samples and representative murine models, have led to a proposed delineation of four major subtypes for SCLC distinguished by differential expression of four key transcriptional regulators (ASCL1, NEUROD1, POU2F3, and YAP1). Our understanding of the biology of SCLC has indeed significantly improved recently due to the continued efforts of the dedicated investigators in this field, but the therapeutic options remain dismal. While recent results from immunotherapy trials are encouraging, most patients demonstrate either primary or rapid acquired resistance to current regimens, highlighting the clear need to improve the effectiveness and expand the scope of current therapeutic strategies. In this opinion article, we will discuss recent developments in the treatment of SCLC, focused on current understanding of the signaling pathways, the role of immunotherapy and targeted therapy, and emerging biomarkers of response to therapy in SCLC.

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“…Recent work has highlighted the potential of CDK7 inhibitors to be used in combination with immunotherapies. The CDK7 inhibitor, YKL-5-124, was shown to elicit immune response signalling in small cell lung cancer (SCLC), activating anti-tumourigenic T cells [131]. In immunocompetent mouse models of SCLC, the combination of YKL-5-124 and anti-PD-1 immune checkpoint inhibition increased overall survival in comparison with either treatment alone, and was further enhanced by the addition of chemotherapeutics (cisplatin and etoposide) [131].…”

Section: B E T I N H I B I T O R S C O M P O U N D S T H a T T A Rmentioning

confidence: 99%

CDK7 inhibitors as anticancer drugs

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et al. 2020

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Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.

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CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer

Cited by 148 publications

References 62 publications

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

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

Targeted Therapies and Biomarkers in Small Cell Lung Cancer

CDK7 inhibitors as anticancer drugs

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