In a new study published in Oncotarget, Hauge et al. found an explanation for why combined inhibition of Chk1 and Wee1 gives synergistic anti-cancer effects.
Inhibitors of Wee1 and Chk1 kinases are currently in clinical trials in combination with radiation- or chemotherapy, due to their roles in inhibition of cell cycle checkpoints and DNA repair. Recent preclinical studies have shown synergistic effects of simultaneous Wee1 and Chk1 inhibition, but the mechanisms behind this synergy were not known.
The authors carried out a flow cytometry based screen to identify compounds that cause increased DNA damage in S-phase when combined with a Wee1 inhibitor. Two Chk1 inhibitors were among the top candidate hits out of 1664 tested compounds, suggesting that simultaneous Wee1 and Chk1 inhibition synergistically enhances S-phase DNA damage. Furthermore, the authors found that this synergy can be explained by distinct functions of Wee1 and Chk1 in regulation of CDK (Cyclin-Dependent-Kinase) and CDC45 (a replication initiation factor), respectively.
This work gives new knowledge about how Chk1 and Wee1 inhibitors work for cancer treatment as single agents and in combination.
Combined inhibition of Wee1 and Chk1 gives synergistic DNA damage in S-phase due to distinct regulation of CDK activity and CDC45 loading.
Hauge S, Naucke C, Hasvold G, Joel M, Rødland GE, Juzenas P, Stokke T, Syljuåsen RG.
Oncotarget. 2016 Dec 22. doi: 10.18632/oncotarget.14089. [Epub ahead of print]