Control of Expression of Key Cell Cycle Enzymes Drives Cell Line-Specific Functions of CDK7 in Human PDAC Cells

Abstract

Inhibition of the dual function cell cycle and transcription kinase CDK7 is known to affect the viability of cancer cells, but the mechanisms underlying cell line-specific growth control remain poorly understood. Here, we employed a previously developed, highly specific small molecule inhibitor that non-covalently blocks ATP binding to CDK7 (LDC4297) to study the mechanisms underlying cell line-specific growth using a panel of genetically heterogeneous human pancreatic tumor lines as model system. Although LDC4297 diminished both transcription rates and CDK T-loop phosphorylation in a comparable manner, some PDAC lines displayed significantly higher sensitivity than others. We focused our analyses on two well-responsive lines (Mia-Paca2 and Panc89) that, however, showed significant differences in their viability upon extended exposure to limiting LDC4297 concentrations. Biochemical and RNAseq analysis revealed striking differences in gene expression and cell cycle control. Especially the downregulation of a group of cell cycle control genes, among them CDK1/2 and CDC25A/C, correlated well to the observed viability differences in Panc89 versus Mia-Paca2 cells. A parallel downregulation of regulatory pathways supported the hypothesis of a feedforward programmatic effect of CDK7 inhibitors, eventually causing hypersensitivity of PDAC lines.

CDK7 in breast cancer: mechanisms of action and therapeutic potential

“…Notably, increased CDK7 expression correlates with a dismal prognosis [31]. Targeting CDK7 has revealed pronounced effects on cancer cell proliferation, migration, invasion, stemness, and drug resistance across malignancies such as breast cancer [32], lung cancer [33], hepatocellular carcinoma [34], thyroid cancer [35], glioblastoma [36], gastric cancer [37], pancreatic cancer [38], gallbladder cancer [39], colorectal cancer [40], osteosarcoma [41], lymphomas [42], leukemia [43], among others. In recent years, a range of specific small molecular inhibitors targeting CDK7 has been synthesized and classified, as detailed in Table 1.…”

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

“…CDK7 has been revealed to have a dual role in the regulation of transcription and cell cycle. 19 PaC is highly addictive to CDK7-dependent transcription. 20 Inhibiting CDK7 potently and selectively weakens the proliferation and viability of human PDAC cells, and represses PDAC progression in preclinical models, by pronouncedly downregulating transcription of genes, including those linked to the NF-κB signalling and mitotic cell cycle.…”

“…CDK7 has been revealed to have a dual role in the regulation of transcription and cell cycle 19 . PaC is highly addictive to CDK7‐dependent transcription 20 .…”