Abstract A42: Prexasertib (LY2606368) is highly active as a monotherapy or in combination with chemotherapy in preclinical models of pediatric bone and soft tissue sarcoma

Abstract

Abstract The serine/threonine kinase checkpoint kinase 1 (CHK1) is a crucial mediator of replication stress and helps maintain genome integrity by governing the S-phase and G2/M cell cycle checkpoints following DNA damage, facilitating DNA repair through homologous recombination, and licensing replication forks during S phase. The CHK1 small-molecule inhibitor prexasertib (LY2606368) is currently under clinical investigation in pediatric cancer patients with recurrent or refractory solid tumors (NCT02808650). Reduced proliferation was observed at low nanomolar concentrations in a panel of pediatric bone and soft tissue sarcoma cell lines. In addition, prexasertib caused DNA damage and cell death in vitro as measured by Western blot analysis and high content imaging. Prexasertib as a monotherapy was superior to doxorubicin or actinomycin D in several cell line-derived and patient-derived xenograft (PDX) models of pediatric soft tissue sarcoma, with two models of alveolar rhabdomyosarcoma (aRMS) demonstrating a complete response to prexasertib; however, acquired resistance to prexasertib was observed. In addition, preclinical PDX mouse models of Ewing’s sarcoma and osteosarcoma typically demonstrated intrinsic resistance to single-agent prexasertib. Importantly, combination with cytotoxic chemotherapy could not only overcome intrinsic prexasertib resistance in vivo, as would be expected given the potential for prexasertib to act as a chemopotentiator, but also prevented the emergence of acquired resistance following single-agent prexasertib treatment. In vitro experiments were performed to evaluate the effect of prexasertib plus chemotherapy on cell proliferation. Future preclinical studies include genomic analysis of pediatric bone and soft tissue sarcoma models to delineate the molecular underpinnings of sensitivity and acquired resistance to prexasertib and to identify predictive biomarkers for response. Citation Format: Caitlin D. Lowery, Wayne Blosser, Michele Dowless, Matthew Renschler, Jennifer Stephens, Richard Beckmann, Louis Stancato. Prexasertib (LY2606368) is highly active as a monotherapy or in combination with chemotherapy in preclinical models of pediatric bone and soft tissue sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A42.