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

Research output: Contribution to journalArticle

64 Scopus citations

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 languageEnglish (US)
Pages (from-to)3870-3884
Number of pages15
JournalCancer research
Volume77
Issue number14
DOIs
StatePublished - Jul 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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