期刊
CANCER RESEARCH
卷 77, 期 14, 页码 3870-3884出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-3409
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类别
资金
- NIH [R01CA207295]
- The University of Texas MD Anderson Cancer Center Small Cell Lung Cancer Working Group
- Abell Hangar Foundation Distinguished Professor Endowment
- Sidney Kimmel Scholar Award
- Free to Breathe
- LUNGevity Foundation
- Uniting Against Lung Cancer
- R. Lee Clark Fellow Award
- Jeanne F. Shelby Scholarship Fund
- MD Anderson Physician Scientist Award
- National Cancer Institute Cancer Clinical Investigator Team Leadership Award [P30 CA016672]
- The Susan G. Komen Foundation
- NIH/National Cancer Institute [P30CA016672]
- NCI Cancer Center Support Grant [P30CA016672]
- North Carolina Lung Cancer Partnership
- [LY2606368]
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.
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