Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.
Cell
; 173(4): 864-878.e29, 2018 05 03.
Article
em En
| MEDLINE
| ID: mdl-29681454
ABSTRACT
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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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Carcinoma Pulmonar de Células não Pequenas
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Proliferação de Células
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Bibliotecas de Moléculas Pequenas
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article