CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Although combined treatment with gemcitabine and albumin-bound paclitaxel has improved the prognosis of PDAC, both intrinsic and acquired chemoresistance remain as severe hurtles towards improved prognosis. Thus, new therapeutic targets and innovative strategies are urgently needed. Methods In this study, we used the KPC mouse model-derived PDAC cell line TB32047 to perform kinome-wide CRISPR-Cas9 loss-of-function screening. Next-generation sequencing and MAGeCK-VISPR analysis were performed to identify candidate genes. We then conducted cell viability, clonogenic, and apoptosis assays and evaluated the synergistic therapeutic effects of cyclin-dependent kinase 7 (CDK7) depletion or inhibition with gemcitabine (GEM) and paclitaxel (PTX) in a murine orthotopic pancreatic cancer model. For mechanistic studies, we performed genome enrichment analysis (GSEA) and Western blotting to identify and verify the pathways that render PDAC sensitive to GEM/PTX therapy. Results We identified several cell cycle checkpoint kinases and DNA damage-related kinases as targets for overcoming chemoresistance. Among them, CDK7 ranked highly in both screenings. We demonstrated that both gene knockout and pharmacological inhibition of CDK7 by THZ1 result in cell cycle arrest, apoptosis induction, and DNA damage at least predominantly through the STAT3-MCL1-CHK1 axis. Furthermore, THZ1 synergized with GEM and PTX in vitro and in vivo, resulting in enhanced antitumor effects. Conclusions Our findings support the application of CRISPR-Cas9 screening in identifying novel therapeutic targets and suggest new strategies for overcoming chemoresistance in pancreatic cancer.

Genome-wide functional CRISPR screen reveals CDK7 as a targetable therapeutic vulnerability for head and neck cancer

“…CDK7 is detected aberrantly overexpressed in different cancer types (15,16). Several CDK7-selective inhibitors have proved e cacy in various preclinical models of breast (18, 19), pancreatic (20,40), and lung cancer (21) among others. Moreover, some CDK7 inhibitors have entered Phase I clinical trials for breast cancers (33,34).…”

CDK7 in breast cancer: mechanisms of action and therapeutic potential

“…Analyzing breast cancer TMAs for CDK7 (n = 945), the study found that patients with high-grade and extensive tumors, or those with recurrent disease, exhibited lower CDK7 expression. Elevated CDK7 levels were instead associated Breast cancer [70], Gastric cancer [54], Osteosarcoma [115], Synovial sarcoma [116], Thyroid carcinoma [117], T cell acute lymphoblastic leukemia [118] No [95], Head and neck squamous cell carcinoma [121], Thyroid cancer [122], Neuroblastoma [123], Glioblastoma [124], Gastrointestinal stromal tumours [125], Pancreatic cancer [126], Hepatocellular carcinoma [127], Gallbladder cancer [39], Cholangiocarcinoma [128], Colorectal cancer [40], Nasopharyngeal carcinoma [129], Prostate cancer [130], Renal cell carcinoma [131], Urothelial carcinoma [132], Bladder cancer [133], Melanoma [134], Osteosarcoma [135], lymphomas [62], Leukemia [43] No with extended BCSS and prolonged time to distant metastasis [67]. This landscape of disparate findings illustrates the complexity of CDK7's role within breast cancer prognosis and highlights the necessity for further refined and targeted investigations.…”

Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic Indicator and Therapeutic Target

“…Indeed, SY-351, a highly selective irreversible CDK7 inhibitor showed a potent effect in splicing modulation 25 . Of note, CDK7 has emerged as a target to address chemoresistance, as revealed by a recent kinome-wide CRISPR-Cas9 loss-of-function screening conducted in the PDAC cell line derived from the KPC mouse model 26 .…”