Broad spectrum activity of the checkpoint kinase 1 inhibitor prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models

Caitlin D. Lowery, Michele Dowless, Matthew Renschler, Wayne Blosser, Alle B. VanWye, Jennifer R. Stephens, Philip W. Iversen, Aimee Bence Lin, Richard P. Beckmann, Kateryna Krytska, Kristina A. Cole, John M. Maris, Douglas S. Hawkins, Brian P. Rubin, Raushan T. Kurmasheva, Peter J Houghton, Richard Gorlick, E. Anders Kolb, Min H. Kang, C. Patrick ReynoldsStephen W. Erickson, Beverly A. Teicher, Malcolm A. Smith, Louis F. Stancato

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2278-2289
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number7
DOIs
StatePublished - Apr 1 2019
Externally publishedYes

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Pediatrics
Neoplasms
Combination Drug Therapy
Heterografts
Sarcoma
DNA Damage
Desmoplastic Small Round Cell Tumor
Alveolar Rhabdomyosarcoma
Rhabdoid Tumor
Drug Therapy
Cell Line
Ewing's Sarcoma
Rhabdomyosarcoma
Osteosarcoma
Checkpoint Kinase 1
Neuroblastoma
Histology
Cell Death
Research Design
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Broad spectrum activity of the checkpoint kinase 1 inhibitor prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models. / Lowery, Caitlin D.; Dowless, Michele; Renschler, Matthew; Blosser, Wayne; VanWye, Alle B.; Stephens, Jennifer R.; Iversen, Philip W.; Lin, Aimee Bence; Beckmann, Richard P.; Krytska, Kateryna; Cole, Kristina A.; Maris, John M.; Hawkins, Douglas S.; Rubin, Brian P.; Kurmasheva, Raushan T.; Houghton, Peter J; Gorlick, Richard; Anders Kolb, E.; Kang, Min H.; Patrick Reynolds, C.; Erickson, Stephen W.; Teicher, Beverly A.; Smith, Malcolm A.; Stancato, Louis F.

In: Clinical Cancer Research, Vol. 25, No. 7, 01.04.2019, p. 2278-2289.

Research output: Contribution to journalArticle

Lowery, CD, Dowless, M, Renschler, M, Blosser, W, VanWye, AB, Stephens, JR, Iversen, PW, Lin, AB, Beckmann, RP, Krytska, K, Cole, KA, Maris, JM, Hawkins, DS, Rubin, BP, Kurmasheva, RT, Houghton, PJ, Gorlick, R, Anders Kolb, E, Kang, MH, Patrick Reynolds, C, Erickson, SW, Teicher, BA, Smith, MA & Stancato, LF 2019, 'Broad spectrum activity of the checkpoint kinase 1 inhibitor prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models', Clinical Cancer Research, vol. 25, no. 7, pp. 2278-2289. https://doi.org/10.1158/1078-0432.CCR-18-2728
Lowery, Caitlin D. ; Dowless, Michele ; Renschler, Matthew ; Blosser, Wayne ; VanWye, Alle B. ; Stephens, Jennifer R. ; Iversen, Philip W. ; Lin, Aimee Bence ; Beckmann, Richard P. ; Krytska, Kateryna ; Cole, Kristina A. ; Maris, John M. ; Hawkins, Douglas S. ; Rubin, Brian P. ; Kurmasheva, Raushan T. ; Houghton, Peter J ; Gorlick, Richard ; Anders Kolb, E. ; Kang, Min H. ; Patrick Reynolds, C. ; Erickson, Stephen W. ; Teicher, Beverly A. ; Smith, Malcolm A. ; Stancato, Louis F. / Broad spectrum activity of the checkpoint kinase 1 inhibitor prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 7. pp. 2278-2289.
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abstract = "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.",
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T1 - Broad spectrum activity of the checkpoint kinase 1 inhibitor prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models

AU - Lowery, Caitlin D.

AU - Dowless, Michele

AU - Renschler, Matthew

AU - Blosser, Wayne

AU - VanWye, Alle B.

AU - Stephens, Jennifer R.

AU - Iversen, Philip W.

AU - Lin, Aimee Bence

AU - Beckmann, Richard P.

AU - Krytska, Kateryna

AU - Cole, Kristina A.

AU - Maris, John M.

AU - Hawkins, Douglas S.

AU - Rubin, Brian P.

AU - Kurmasheva, Raushan T.

AU - Houghton, Peter J

AU - Gorlick, Richard

AU - Anders Kolb, E.

AU - Kang, Min H.

AU - Patrick Reynolds, C.

AU - Erickson, Stephen W.

AU - Teicher, Beverly A.

AU - Smith, Malcolm A.

AU - Stancato, Louis F.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

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