CDK7 inhibition by SY5609 suppresses tumor growth in gastric cancer through inhibiting RNA pol II mediated transcription and Hippo/YAP1 signaling

Background: Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases that catalyze protein phosphorylation to regulate key cellular processes. CDK7 is transcription-associated CDK which participates in both transcriptional regulation and cell cycle control. CDK7 forms a complex with cyclin H to phosphorylate the C-terminal domain (CTD) of RNA polymerase II, thereby promoting transcription initiation and elongation. In addition, CDK7 has been shown to phosphorylate the Hippo pathway coactivator YAP1 at serine 128 in mammalian cells, leading to YAP stabilization and enhanced its transcriptional activity. These findings suggest that CDK7 may represent an attractive therapeutic target. SY5609 treatment demonstrated acceptable tolerability and preliminary antitumor activity in patients with advanced pancreatic cancer. However, the expression profile of CDK7, its association with Hippo/YAP1 signaling, and its therapeutic value in advanced gastric cancer (GC) remain poorly understood. This study aimed to explore the anticancer effects of CDK7 inhibition and its potential interaction with Hippo/YAP1 signaling in GC model. Methods: CDK7 expression was evaluated by immunohistochemistry and Western blotting in human GC tissues, patient-derived xenografts (PDXs), and GC cell lines, and further analyzed using public datasets. Functional assays, including cell proliferation, invasion, colony formation, tumor sphere formation and In vivo antitumor efficacy were performed to assess the effects of CDK7 inhibition by SY5609. Results: CDK7 expression was significantly elevated in GC tumor tissues compared with adjacent normal tissues in two public datasets (cistrome.shinyapps.io/timer; GSE33335). SY5609 treatment markedly reduced cell viability and colony formation in a dose-dependent manner in GC cell lines. It also inhibited migration and tumor spheroid formation at low concentrations. Mechanistically, SY5609 decreased RNA Pol II mediated transcription and induced apoptosis. SY5609 also significantly inhibited TEAD-YAP1 transcriptional activity. Unexpectedly, SY5609 increased PD-L1 mRNA and protein expression in GC cell lines, suggesting a potential rationale for combination therapy with PD-1/PD-L1 immune checkpoint blockade. Oral administration of SY5609 significantly suppressed tumor growth and reduced tumor weight in PDX models without affecting mouse body weight. Conclusion: Mechanistically, SY5609 treatment suppressed transcription and induced apoptosis by decreasing RNA Pol II Ser2/Ser5 phosphorylation, and reduced YAP1-TEAD transcriptional activity. Thus, targeting CDK7 with SY5606 represents a promising therapeutic strategy for advanced gastric cancer and may provide synergistic benefit when combined with immune checkpoint inhibitors.