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. Epub 2018 Apr 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cytochrome P450 Family 4 / deficiency
  • Cytochrome P450 Family 4 / genetics
  • Drug Discovery
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Glucocorticoids / pharmacology
  • Glucose Transport Proteins, Facilitative / antagonists & inhibitors
  • Glucose Transport Proteins, Facilitative / genetics
  • Glucose Transport Proteins, Facilitative / metabolism
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mutation
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / metabolism
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*

Substances

  • Glucocorticoids
  • Glucose Transport Proteins, Facilitative
  • KEAP1 protein, human
  • KRAS protein, human
  • Kelch-Like ECH-Associated Protein 1
  • Microtubule-Associated Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • NOTCH2 protein, human
  • NR3C1 protein, human
  • RNA, Small Interfering
  • Receptor, Notch2
  • Receptors, Glucocorticoid
  • SLC2A8 protein, human
  • Small Molecule Libraries
  • TTC21B protein, human
  • Cytochrome P450 Family 4
  • CYP4F11 protein, human
  • Proto-Oncogene Proteins p21(ras)