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Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer

 Elizabeth A McMillan  ;  Myung-Jeom Ryu  ;  Caroline H Diep  ;  Saurabh Mendiratta  ;  Jean R Clemenceau  ;  Rachel M Vaden  ;  Ju-Hwa Kim  ;  Takashi Motoyaji  ;  Kyle R Covington  ;  Michael Peyton  ;  Kenneth Huffman  ;  Xiaofeng Wu  ;  Luc Girard  ;  Yeojin Sung  ;  Pei-Hsaun Chen  ;  Prema L Mallipeddi  ;  Joo Young Lee  ;  Jordan Hanson  ;  Sukesh Voruganti  ;  Yunku Yu  ;  Sunho Park  ;  Jessica Sudderth  ;  Christopher DeSevo  ;  Donna M Muzny  ;  HarshaVardhan Doddapaneni  ;  Adi Gazdar  ;  Richard A Gibbs  ;  Tae-Hyun Hwang  ;  John V Heymach  ;  Ignacio Wistuba  ;  Kevin R Coombes  ;  Noelle S Williams  ;  David A Wheeler  ;  John B MacMillan  ;  Ralph J Deberardinis  ;  Michael G Roth  ;  Bruce A Posner  ;  John D Minna  ;  Hyun Seok Kim  ;  Michael A White 
 CELL, Vol.173(4) : 864-878.e29, 2018 
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KRAS mutant ; NRF2 signaling ; cancer target identification ; chemical biology ; ciliogenesis ; glucocorticoid therapies ; lung cancer ; serine biosynthesis
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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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
Lee, Joo Young(이주영)
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