Prexasertib, a highly potent Chk1 inhibitor, has shown remarkable single-agent activity (IC50 < 5 nmol/L) in a subset of head and neck cancer (HNSCC) cells that are genomically predisposed to replication stress. Nevertheless, a broader application of this therapeutic strategy in HNSCC is hindered because many HNSCC cells lack innate susceptibility to replication stress and exhibit much higher IC50 values for prexasertib. Here we report that gemcitabine cotreatment markedly augments the therapeutic efficacy of prexasertib in HNSCC cells that are recalcitrant/less sensitive to Chk1 inhibition monotherapy. Mechanistic investigations revealed perturbation in the S phase progression and induction of replication stress markers that associated with decreased colony survival upon gemcitabine and prexasertib combination treatment. These results indicate that therapeutic utility of prexasertib could be further expanded in HNSCC through a combination treatment with gemcitabine.

Citation Format: Mayur A. Gadhikar, Jeffrey N. Myers. Gemcitabine cotreatment enhances the therapeutic effect of prexasertib in HNSCC cells that are less sensitive to Chk1 inhibition single-agent therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A073.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.