Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single Agent Anticancer Therapy
Menée in vitro et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un composé appelé MK-1775, un inhibiteur de la kinase WEE1
Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell cycle arrest and proper DNA repair. However, WEE1 is also essential for unperturbed cell division in the absence of extrinsic insult. Here we investigate the anticancer potential of a WEE1 inhibitor, independent of chemotherapy, and explore a possible cellular context underlying sensitivity to WEE1 inhibition. We demonstrate that MK-1775, a potent and selective ATP-competitive inhibitor of WEE1, is cytotoxic across a broad panel of tumor cell lines and induces DNA double strand breaks. MK-1775-induced DNA damage occurs without added chemotherapy or radiation in S-phase cells and relies on active DNA replication. At tolerated doses, MK-1775 treatment leads to xenograft tumor growth inhibition or regression. To begin addressing potential response markers for MK-1775 monotherapy we focused on PKMYT1, a kinase functionally related to WEE1. Knockdown of PKMYT1 lowers the EC50 of MK-1775 by 5-fold but has no effect on the cell-based response to other cytotoxic drugs. Additionally, knockdown of PKMYT1 increases markers of DNA damage, γH2AX and pCHK1S345, induced by MK-1775. In a post-hoc analysis of 305 cell lines treated with MK-1775, we found expression of PKMYT1 was below average in 73% of the 33 most sensitive cell lines. Our findings provide rationale for WEE1 inhibition as a potent anticancer therapy independent of a genotoxic partner and suggest that low PKMYT1 expression could serve as an enrichment biomarker for MK-1775 sensitivity.
http://mct.aacrjournals.org/content/early/2013/05/22/1535-7163.MCT-13-0025.abstract