Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death

• DOI: 10.1038/s41389-019-0147-x
• Publication Date: 2019-06-17T12:02:57Z
• Authors: Anne M. van Harten; Marijke Buijze; Richard van der Mast; Martin A. Rooimans; Sanne R. Martens-...; Costa Bachas; Arjen Brink; Marijke Stigter-v...; Rob M. F. Wolthuis; Ruud H. Brakenhoff
• Keywords: Squamous cell cancer

Head and neck squamous cell carcinomas (HNSCCs) coincide with poor survival rates. The lack of driver oncogenes complicates the development targeted treatments for HNSCC. Here, we follow-up on two previous genome-wide RNA microRNA interference screens in HNSCC to cross-examine tumor-specific lethality by targeting ATM, ATR, CHEK1, or CHEK2. Our results uncover CHEK1 as most promising target expression is essential across a panel lines but redundant growth untransformed oral keratinocytes fibroblasts. LY2603618 (Rabusertib), which specifically targets Chk1 kinase, kills cells effectively specifically. findings show that depend Chk1-mediated signaling progress through S-phase successfully. inhibition coincides stalled DNA replication, replication fork collapses, accumulation damage. We further leads bimodal killing. In sensitive lines, apoptosis induced S-phase, whereas more resistant manage bypass replication-associated apoptosis, accumulate chromosomal breaks become lethal subsequent mitosis. Interestingly, CDK1 correlates treatment outcome. Moreover, sensitivity requires functional CDK4/6 drive cycle progression, arguing against combining inhibitors CDK inhibitors. contrast, Wee1 inhibitor Adavosertib progresses thereby increases lines. conclude has key molecule regulation very therapeutic target. death provide potential efficacy biomarker combination therapy clinical setting.