American Association for Cancer Research
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Supplementary Figure and Figure Legends from CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib

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posted on 2023-03-31, 00:44 authored by 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

This file contains the supplementary figures and figure legends. Figure S1: CHK1 overexpression and LY2606368 targeting efficacy in SCLC. Figure S2:Combinatorial effect of LY2606368 and cisplatin. Figure S3: Anti-tumor efficacy of LY2606368. Figure S4: Effect of LY2606368 in platinum-resistant SCLC models. Figure S5: Combinatorial effect of LY2606368 and olaparib. Figure S6 and S7: Proteomic biomarkers of LY2606368 response. Figure S8: MYC expression predicts sensitivity to LY2606368.

Funding

NIH

University of Texas MD Anderson Cancer Center Small Cell Lung Cancer Working Group and Abell Hangar Foundation Distinguished Professor Endowment

Sidney Kimmel Scholar Award

Free to Breathe

North Carolina Lung Cancer Partnership

LUNGevity Foundation

Uniting Against Lung Cancer

Jeanne F. Shelby Scholarship Fund

MD Anderson Physician Scientist Award

National Cancer Institute Cancer Clinical Investigator Team Leadership Award

The Susan G. Komen Foundation award

Pharmaceutical Chemistry Facility at MD Anderson

NIH/National Cancer Institute

NCI Cancer Center Support Grant

History

ARTICLE ABSTRACT

Effective targeted therapies for small-cell lung cancer (SCLC), the most aggressive form of lung cancer, remain urgently needed. Here we report evidence of preclinical efficacy evoked by targeting the overexpressed cell-cycle checkpoint kinase CHK1 in SCLC. Our studies employed RNAi-mediated attenuation or pharmacologic blockade with the novel second-generation CHK1 inhibitor prexasertib (LY2606368), currently in clinical trials. In SCLC models in vitro and in vivo, LY2606368 exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models. Proteomic analysis identified CHK1 and MYC as top predictive biomarkers of LY2606368 sensitivity, suggesting that CHK1 inhibition may be especially effective in SCLC with MYC amplification or MYC protein overexpression. Our findings provide a preclinical proof of concept supporting the initiation of a clinical efficacy trial in patients with platinum-sensitive or platinum-resistant relapsed SCLC. Cancer Res; 77(14); 3870–84. ©2017 AACR.

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