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 YuSunho Park, Jessica Sudderth, Christopher DeSevo, Donna M. Muzny, Harsha Vardhan 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

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22 Scopus citations

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. Application of a chemistry-first approach matches chemicals with targetable, diverse genetic lesions and cancer-promoting mechanisms in human lung cancer, providing guidance for development of personalized cancer treatment.

Original languageEnglish (US)
Pages (from-to)864-878.e29
JournalCell
Volume173
Issue number4
DOIs
StatePublished - May 3 2018

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Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

McMillan, E. A., Ryu, M. J., Diep, C. H., Mendiratta, S., Clemenceau, J. R., Vaden, R. M., Kim, J. H., Motoyaji, T., Covington, K. R., Peyton, M., Huffman, K., Wu, X., Girard, L., Sung, Y., Chen, P. H., Mallipeddi, P. L., Lee, J. Y., Hanson, J., Voruganti, S., ... White, M. A. (2018). Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer. Cell, 173(4), 864-878.e29. https://doi.org/10.1016/j.cell.2018.03.028