期刊
CELL
卷 173, 期 4, 页码 864-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.03.028
关键词
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资金
- NIH [CA197717, CA176284, CA70907, CA142543]
- CPRIT [RP120732, RP110708]
- Robert Welch Foundation [I-1414]
- Korea Health Technology R & D project through the Korea Health Industry Development Institute [HI14C1324]
- National R&D Program for Cancer Control - Ministry of Health & Welfare, Republic of Korea [1420100]
- NIH training grant [5T32GM8203-27, 5T32CA124334-09]
- CPRIT training grant [RP140110]
- NATIONAL CANCER INSTITUTE [T32CA124334, R35CA197717, P50CA070907, P30CA016058, P30CA142543, U01CA176284, R35CA220449] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008203] Funding Source: NIH RePORTER
Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.
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