Fig. 7: Schematic summary of molecular mechanism.

Schematic summary of molecular mechanism underlying Chk1 sensitivity in HNSCC. When Chk1 is inhibited, cells accumulate in S-phase due to DNA replication problems. This results in increased DNA damage (γH2Ax Ser139). Sensitive cells initiate a caspase cascade in S- or early G2-phase, to initiate apoptotic cell death. These cells typically harbor a low intrinsic CDK1 level. Less-sensitive cells encounter comparable DNA replication problems due to Chk1-dependency, but do not initiate apoptosis and proceed into mitosis with incomplete DNA replication and unrepaired DNA damage. This results in chromosomal breaks causing death in mitosis during subsequent cell division. Primary cells lack the strict Chk1-dependency during DNA replication, due to a tightly regulated cell cycle control, therefore, primary cells enable to successfully continue into mitosis when Chk1 is inhibited. Our data further shows that the efficacy of Chk1 inhibition in HNSCC is dependent on cell cycle progression. Therefore, functional CDK4/6 is required for S-phase entry and functional CDK1 is necessary for S-phase progression and subsequent mitotic entry, thereby facilitating the accumulation of DNA damage. The combination of Chk1 inhibitors with therapies that hamper cell cycle progression should not be considered for clinical research, but combination with inhibitors that support cell cycle progression seems to have more than added value