2. Academic Validation
  3. Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer

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

  • Cell. 2018 May 3;173(4):864-878.e29. doi: 10.1016/j.cell.2018.03.028.
Elizabeth A McMillan 1,  Myung-Jeom Ryu 2,  Caroline H Diep 1,  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 9,  Richard A Gibbs 4,  Tae-Hyun Hwang 8,  John V Heymach 10,  Ignacio Wistuba 11,  Kevin R Coombes 12,  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 13,  Hyun Seok Kim 14,  Michael A White 15
Affiliations

Affiliations

  • 1 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
  • 3 Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Kanagawa, Japan.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5 Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 6 Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 9 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 10 Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 11 Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 12 Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.
  • 13 Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 14 Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. Electronic address: [email protected].
  • 15 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 29681454 DOI: 10.1016/j.cell.2018.03.028
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.

Keywords

KRAS mutant; NRF2 signaling; cancer target identification; chemical biology; ciliogenesis; glucocorticoid therapies; lung cancer; serine biosynthesis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139047
    98.67%, GLUT8 Inhibitor