김현석 (연세대학교 의과대학)

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연세대학교 의과대학

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Cell, VOLUME 173, ISSUE 4, P864-878.E29. Published: April 19, 2018 | DOI: https://doi.org/10.1016/j.cell.2018.03.028 Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer

Elizabeth A. McMillan,¹ Myung-Jeom Ryu,^2,14 Caroline H. Diep,^1,14 Saurabh Mendiratta,¹ Jean R. Clemenceau,¹ Rachel M. Vaden,¹ Ju-Hwa Kim,² Takashi Motoyaji,³ Kyle R. Covington,⁴ Michael Peyton,⁵ Kenneth Huffman,⁵ Xiaofeng Wu,¹ Luc Girard,⁵ Yeojin Sung,² Pei-Hsaun Chen,⁶ Prema L. Mallipeddi,⁷ Joo Young Lee,² Jordan Hanson,⁷ Sukesh Voruganti,⁷ Yunku Yu,⁸ Sunho Park,⁸ Jessica Sudderth,⁶ Christopher DeSevo,¹ Donna M. Muzny,⁴ HarshaVardhan Doddapaneni,⁴ Adi Gazdar,¹² Richard A. Gibbs,⁴ Tae-Hyun Hwang,⁸ John V. Heymach,⁹ Ignacio Wistuba,¹⁰ Kevin R. Coombes,¹¹ Noelle S. Williams,⁷ David A. Wheeler,⁴ John B. MacMillan,⁷ Ralph J. Deberardinis,⁶ Michael G. Roth,⁷ Bruce A. Posner,⁷ John D. Minna,^5,* Hyun Seok Kim,^2,* and Michael A. White^1,13,*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 Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA

¹⁰Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA

¹¹Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA

¹²Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

¹³Lead Contact

¹⁴These authors contributed equally

^*Correspondence: John D. Minna, Hyun Seok Kim, Michael A. White

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.

논문정보

TOP52018년 선정

형식Research article
게재일2018년 04월 (BRIC 등록일 2018-04-26)
연구진국내(교신)+국외 연구진
분야 의약학 > 종양의학

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