Differential Regulation of Cancer Progression by CDK4/6 Plays a Central Role in DNA Replication and Repair Pathways

Abstract

Although the cyclin-dependent kinases CDK4 and CDK6 play fundamental roles in cancer, the specific pathways and downstream targets by which they exert their tumorigenic effects remain elusive. In this study, we uncover distinct and novel functions for these kinases in regulating tumor formation and metastatic colonization in various solid tumors, including those of the breast, prostate, and pancreas. Combining in vivo CRISPR-based CDK4 and CDK6 gene editing with pharmacologic inhibition approaches in orthotopic transplantation and patient-derived xenograft preclinical models, we defined clear functions for CDK4 and CDK6 in facilitating tumor growth and progression in metastatic cancers. Transcriptomic profiling of CDK4/6 CRISPR knockouts in breast cancer revealed these two kinases to regulate cancer progression through distinct mechanisms. CDK4 regulated prometastatic inflammatory cytokine signaling, whereas CDK6 mainly controlled DNA replication and repair processes. Inhibition of CDK6 but not CDK4 resulted in defective DNA repair and increased DNA damage. Multiple CDK6 DNA replication/repair genes were not only associated with cancer subtype, grades, and poor clinical outcomes, but also facilitated primary tumor growth and metastasis in vivo. CRISPR-based genomic deletion of CDK6 efficiently blocked tumor formation and progression in preestablished cell- and patient-derived xenograft preclinical models of breast cancer, providing a potential novel targeted therapy for these deadly tumors. Significance: In-depth transcriptomic analysis identifies cyclin-dependent kinases CDK4 and CDK6 as regulators of metastasis through distinct signaling pathways and reveals the DNA replication/repair pathway as central in promoting these effects.

A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer

“…Our data indicated that ZC-22 notably induced formation of γH2A.X foci in breast and ovarian cancer cells ( Figure 3 D,E). Interestingly, ZC-22 induced stronger DNA damage responses (as indicated by the level of γH2A.X and percentage of cells positive for γH2A.X foci) than Olaparib ( Figure 3 C–E), which was consistent with the previous studies showing that CDK4/6 inhibition impaired HR pathway [ 30 , 31 , 32 ] and consequently aggravated PARPi-induced DNA damage.…”

“…Recently, therapeutic synergy for combination of CDK4/6i and PARPi has been demonstrated in various solid tumors, including those of the breast, ovarian, and pancreas [ 22 , 23 , 48 ], which provides a promising approach for treatment of these cancers regardless HR status. In fact, current evidences indicate that inhibition of CDK6 but not CDK4 results in defective DNA repair and increased DNA damage, suggesting a role of CDK6 in controlling DNA replication and repair processes [ 30 ]. All together, these studies support our findings that combination of CDK4/6 and PARP inhibition by ZC-22 displays anti-tumor efficacy in breast and ovarian cancers beyond HR deficiency.…”

The Immunological Role of CDK4/6 and Potential Mechanism Exploration in Ovarian Cancer

“…First, we find that CDK4/6 are overexpressed in a variety of tumor tissues, including OC, and that high expression of CDK4/ 6 is associated with a poor prognosis in OC patients. Dai et al propose that CDK4 regulates prometastatic inflammatory cytokine signaling, whereas CDK6 mainly controls DNA replication and repair processes, indicating that CDK4 and CDK6 facilitate tumor growth and progression in multiple cancers (18).…”

Identification and Validation of Autophagy-Related Genes as Potential Biomarkers and Therapeutic Targets in Atrial Fibrillation

“…These targets are mainly regulatory factors related to inflammation, DNA replication and repair, cellular senescence, cell cycle, and so forth. [29][30][31][32] Myocardial fibrosis is one of the important mechanisms for the occurrence of AF, and these proteins may indirectly participate in the regulation of AF through myocardial fibrosis. The greatest number Overactivation of TP53 pathway in cardiomyocytes induces myocardial fibrosis.…”