Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models.

Autor:	Lowery CD; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., Dowless M; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., Renschler M; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., Blosser W; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., VanWye AB; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., Stephens JR; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., Iversen PW; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., Lin AB; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., Beckmann RP; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana., Krytska K; The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Cole KA; The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Maris JM; The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Hawkins DS; Division of Hematology/Oncology, Seattle Children's Hospital, Seattle, Washington., Rubin BP; Departments of Pathology and Cancer Biology, Robert J Tomsich Pathology and Laboratory Medicine Institute and Cleveland Clinic, Cleveland, Ohio., Kurmasheva RT; Greehey Children's Cancer Research Institute, San Antonio, Texas., Houghton PJ; Greehey Children's Cancer Research Institute, San Antonio, Texas., Gorlick R; MD Anderson Cancer Center, Houston, Texas., Kolb EA; Nemours Center for Cancer and Blood Disorders, Wilmington, Delaware., Kang MH; Texas Tech University Health Sciences Center, Lubbock, Texas., Reynolds CP; Texas Tech University Health Sciences Center, Lubbock, Texas., Erickson SW; RTI International, Research Triangle Park, North Carolina., Teicher BA; National Cancer Institute, Bethesda, Maryland., Smith MA; National Cancer Institute, Bethesda, Maryland., Stancato LF; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana. stancato_louis@lilly.com.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Apr 01; Vol. 25 (7), pp. 2278-2289. Date of Electronic Publication: 2018 Dec 18.
DOI:	10.1158/1078-0432.CCR-18-2728
Abstrakt:	Purpose: Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested in a large panel of preclinical models of pediatric solid malignancies alone or in combination with chemotherapy. Experimental Design: DNA damage and changes in cell signaling following in vitro prexasertib treatment in pediatric sarcoma cell lines were analyzed by Western blot and high content imaging. Antitumor activity of prexasertib as a single agent or in combination with different chemotherapies was explored in cell line-derived (CDX) and patient-derived xenograft (PDX) mouse models representing nine different pediatric cancer histologies. Results: Pediatric sarcoma cell lines were highly sensitive to prexasertib treatment in vitro , resulting in activation of the DNA damage response. Two PDX models of desmoplastic small round cell tumor and one malignant rhabdoid tumor CDX model responded to prexasertib with complete regression. Prexasertib monotherapy also elicited robust responses in mouse models of rhabdomyosarcoma. Concurrent administration with chemotherapy was sufficient to overcome innate resistance or prevent acquired resistance to prexasertib in preclinical models of neuroblastoma, osteosarcoma, and Ewing sarcoma, or alveolar rhabdomyosarcoma, respectively. Conclusions: Prexasertib has significant antitumor effects as a monotherapy or in combination with chemotherapy in multiple preclinical models of pediatric cancer. These findings support further investigation of prexasertib in pediatric malignancies. (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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