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김현석(의생명과학부) Cell
등록일 : 2018-04-30 오전 10:29:00       조회 : 330
첨   부 :
제1저자 McMillan EA(UT Southwestern)
교신저자 김현석(의생명과학부) Minna JD(UT Southwestern) White MA(UT Southwestern)

Cell. 2018 Apr 11. pii: S0092-8674(18)30308-8. doi: 10.1016/j.cell.2018.03.028. [Epub ahead of print]
Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.
McMillan EA1, Ryu MJ2, Diep CH1, Mendiratta S1, Clemenceau JR1, Vaden RM1, Kim JH2, Motoyaji T3, Covington KR4, Peyton M5, Huffman K5, Wu X1, Girard L5, Sung Y2, Chen PH6, Mallipeddi PL7, Lee JY2, Hanson J7, Voruganti S7, Yu Y8, Park S8, Sudderth J6, DeSevo C1, Muzny DM4, Doddapaneni H4, Gazdar A9, Gibbs RA4, Hwang TH8, Heymach JV10, Wistuba I11, Coombes KR12, Williams NS7, Wheeler DA4, MacMillan JB7, Deberardinis RJ6, Roth MG7, Posner BA7, Minna JD13, Kim HS14, White MA15.

Author information
1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.2Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.3Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Kanagawa, Japan.4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.5Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.6Children''s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.7Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.8Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.10Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.11Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.12Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.13Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: john.minna@utsouthwestern.edu.14Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. Electronic address: hsfkim@yuhs.ac.15Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: michael.white@utsouthwestern.edu.

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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