CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib

Triparna Sen; Pan Tong; C. Allison Stewart; Sandra Cristea; Aly Valliani; David S. Shames; Abena B. Redwood; You Hong Fan; Lerong Li; Bonnie S. Glisson; John D. Minna; Julien Sage; Don L. Gibbons; Helen Piwnica-Worms; John V. Heymach; Jing Wang; Lauren Averett Byers

doi:10.1158/0008-5472.CAN-16-3409

CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib

Triparna Sen, Pan Tong, C. Allison Stewart, Sandra Cristea, Aly Valliani, David S. Shames, Abena B. Redwood, You Hong Fan, Lerong Li, Bonnie S. Glisson, John D. Minna, Julien Sage, Don L. Gibbons, Helen Piwnica-Worms, John V. Heymach, Jing Wang, Lauren Averett Byers

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Abstract

Effective targeted therapies for small-cell lung cancer (SCLC), cisplatin or the PARP inhibitor olaparib, and improved the the most aggressive form of lung cancer, remain urgently response of platinum-resistant models. Proteomic analysis needed. Here we report evidence of preclinical efficacy evoked identified CHK1 and MYC as top predictive biomarkers of by targeting the overexpressed cell-cycle checkpoint kinase LY2606368 sensitivity, suggesting that CHK1 inhibition may CHK1 in SCLC. Our studies employed RNAi-mediated atten-be especially effective in SCLC with MYC amplification or MYC uation or pharmacologic blockade with the novel second-protein overexpression. Our findings provide a preclinical generation CHK1 inhibitor prexasertib (LY2606368), currently proof of concept supporting the initiation of a clinical efficacy in clinical trials. In SCLC models in vitro and in vivo, LY2606368 trial in patients with platinum-sensitive or platinum-resistant exhibited strong single-agent efficacy, augmented the effects of relapsed SCLC.

Original language	English (US)
Pages (from-to)	3870-3884
Number of pages	15
Journal	Cancer Research
Volume	77
Issue number	14
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-3409
State	Published - Jul 15 2017

ASJC Scopus subject areas

Oncology
Cancer Research

MD Anderson CCSG core facilities

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10.1158/0008-5472.CAN-16-3409

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Sen, T., Tong, P., Stewart, C. A., Cristea, S., Valliani, A., Shames, D. S., Redwood, A. B., Fan, Y. H., Li, L., Glisson, B. S., Minna, J. D., Sage, J., Gibbons, D. L., Piwnica-Worms, H., Heymach, J. V., Wang, J., & Byers, L. A. (2017). CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib. Cancer Research, 77(14), 3870-3884. https://doi.org/10.1158/0008-5472.CAN-16-3409

Sen, T, Tong, P, Stewart, CA, Cristea, S, Valliani, A, Shames, DS, Redwood, AB, Fan, YH, Li, L, Glisson, BS, Minna, JD, Sage, J, Gibbons, DL , Piwnica-Worms, H , Heymach, JV , Wang, J & Byers, LA 2017, 'CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib', Cancer Research, vol. 77, no. 14, pp. 3870-3884. https://doi.org/10.1158/0008-5472.CAN-16-3409

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title = "CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib",

abstract = "Effective targeted therapies for small-cell lung cancer (SCLC), cisplatin or the PARP inhibitor olaparib, and improved the the most aggressive form of lung cancer, remain urgently response of platinum-resistant models. Proteomic analysis needed. Here we report evidence of preclinical efficacy evoked identified CHK1 and MYC as top predictive biomarkers of by targeting the overexpressed cell-cycle checkpoint kinase LY2606368 sensitivity, suggesting that CHK1 inhibition may CHK1 in SCLC. Our studies employed RNAi-mediated atten-be especially effective in SCLC with MYC amplification or MYC uation or pharmacologic blockade with the novel second-protein overexpression. Our findings provide a preclinical generation CHK1 inhibitor prexasertib (LY2606368), currently proof of concept supporting the initiation of a clinical efficacy in clinical trials. In SCLC models in vitro and in vivo, LY2606368 trial in patients with platinum-sensitive or platinum-resistant exhibited strong single-agent efficacy, augmented the effects of relapsed SCLC.",

author = "Triparna Sen and Pan Tong and Stewart, {C. Allison} and Sandra Cristea and Aly Valliani and Shames, {David S.} and Redwood, {Abena B.} and Fan, {You Hong} and Lerong Li and Glisson, {Bonnie S.} and Minna, {John D.} and Julien Sage and Gibbons, {Don L.} and Helen Piwnica-Worms and Heymach, {John V.} and Jing Wang and Byers, {Lauren Averett}",

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doi = "10.1158/0008-5472.CAN-16-3409",

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AU - Sen, Triparna

AU - Tong, Pan

AU - Stewart, C. Allison

AU - Cristea, Sandra

AU - Valliani, Aly

AU - Shames, David S.

AU - Redwood, Abena B.

AU - Fan, You Hong

AU - Li, Lerong

AU - Glisson, Bonnie S.

AU - Minna, John D.

AU - Sage, Julien

AU - Gibbons, Don L.

AU - Piwnica-Worms, Helen

AU - Heymach, John V.

AU - Wang, Jing

AU - Byers, Lauren Averett

PY - 2017/7/15

Y1 - 2017/7/15

N2 - Effective targeted therapies for small-cell lung cancer (SCLC), cisplatin or the PARP inhibitor olaparib, and improved the the most aggressive form of lung cancer, remain urgently response of platinum-resistant models. Proteomic analysis needed. Here we report evidence of preclinical efficacy evoked identified CHK1 and MYC as top predictive biomarkers of by targeting the overexpressed cell-cycle checkpoint kinase LY2606368 sensitivity, suggesting that CHK1 inhibition may CHK1 in SCLC. Our studies employed RNAi-mediated atten-be especially effective in SCLC with MYC amplification or MYC uation or pharmacologic blockade with the novel second-protein overexpression. Our findings provide a preclinical generation CHK1 inhibitor prexasertib (LY2606368), currently proof of concept supporting the initiation of a clinical efficacy in clinical trials. In SCLC models in vitro and in vivo, LY2606368 trial in patients with platinum-sensitive or platinum-resistant exhibited strong single-agent efficacy, augmented the effects of relapsed SCLC.

AB - Effective targeted therapies for small-cell lung cancer (SCLC), cisplatin or the PARP inhibitor olaparib, and improved the the most aggressive form of lung cancer, remain urgently response of platinum-resistant models. Proteomic analysis needed. Here we report evidence of preclinical efficacy evoked identified CHK1 and MYC as top predictive biomarkers of by targeting the overexpressed cell-cycle checkpoint kinase LY2606368 sensitivity, suggesting that CHK1 inhibition may CHK1 in SCLC. Our studies employed RNAi-mediated atten-be especially effective in SCLC with MYC amplification or MYC uation or pharmacologic blockade with the novel second-protein overexpression. Our findings provide a preclinical generation CHK1 inhibitor prexasertib (LY2606368), currently proof of concept supporting the initiation of a clinical efficacy in clinical trials. In SCLC models in vitro and in vivo, LY2606368 trial in patients with platinum-sensitive or platinum-resistant exhibited strong single-agent efficacy, augmented the effects of relapsed SCLC.

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CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib

Abstract

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MD Anderson CCSG core facilities

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