This file contains additional details of materials and methods used in this study like SCLC cell line authentication, targeted knockdown of CHK1 and MYC, PCR, cell viability aasay, cell cycle analysis, generation of tumor models, RPPA and immunofluorescence.
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
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.
