Abstract IA20: Exploiting CDK2-driven replication stress to repurpose cancer chemotherapy

Cyclin-dependent kinase 2 (CDK2) coordinates diverse process, including cell cycle entry and progression, DNA replication, and DNA damage and replication stress responses. Cancers frequently contain mutations in genes that regulate CDK2, which is also activated by oncogenic signaling. Because cancers have abnormally high CDK2 activity, most therapeutic strategies seek to inhibit CDK2. Our studies of CDK2 function during replication stress suggest an alternate approach: to harness high CDK2 activity as a therapeutic modality to cause irreparable DNA damage. In order to study the functions of CDK2 inhibitory phosphorylation without perturbing other cell cycle proteins, we used gene targeting in human cells to mutate the endogenous CDK2 T14 and Y15 Wee1 phosphorylation sites. CDK2AF cells exhibited abnormal G1 progression, abnormal DNA replication dynamics, and genome instability, indicating essential regulatory roles for CDK2 inhibitory phosphorylation in these processes. Most strikingly, cells that cannot inhibit CDK2 during stalled S-phase rapidly accumulate massive and irreparable DNA damage and double stranded DNA breaks (termed CDK2-dependent replication stress failure). Importantly, even transient S-phase arrest produces irreversible DNA damage and permanent cell cycle exit, and genetic and pharmacologic studies revealed that that persistent CDK2 activity is both necessary and sufficient to drive replication stress failure. CDK2 inhibitory phosphorylation is thus essentia...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Replication Stress and DNA Damage Response: Oral Presentations - Invited Abstracts Source Type: research