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An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules

Amrita Basu1, Nicole E Bodycombe1, Jaime H Cheah1

  • 1The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

Cell
|September 3, 2013
PubMed

Insights

Researchers profiled 242 cancer cell lines (CCLs) to find new drug targets. They discovered a link between specific gene mutations and sensitivity to small-molecule drugs, aiding personalized cancer therapy.

Area of Science:

  • Genomics
  • Pharmacology
  • Cancer Biology

Background:

  • Targeted therapies show high clinical response rates in cancer patients with specific genomic alterations.
  • Cancer cell line (CCL) profiling is being explored to identify novel biomarkers for small-molecule drug sensitivity.

Purpose of the Study:

  • To quantitatively measure the sensitivity of 242 genomically characterized CCLs to a set of 354 small molecules.
  • To uncover protein dependencies that associate with specific cancer-genomic alterations and can be targeted by small molecules.
  • To create a resource for correlating genetic features to drug sensitivity and controlling for CCL profiling confounders.

Main Methods:

  • Quantitative sensitivity measurement of 242 cancer cell lines (CCLs) against 354 small molecules.
  • Genomic characterization of the tested CCLs.
  • Development of the Cancer Therapeutics Response Portal (CTRP) for data correlation and analysis.

Main Results:

  • Identification of protein dependencies linked to specific cancer-genomic alterations.
  • Discovery of associations between genetic features and small-molecule sensitivity.
  • A candidate dependency was found: activating mutations in β-catenin correlate with sensitivity to navitoclax (a Bcl-2 family antagonist).

Conclusions:

  • The study provides a valuable resource for identifying novel therapeutic hypotheses.
  • The findings accelerate the discovery of drugs matched to cancer patients based on their specific genotype and lineage.
  • The Cancer Therapeutics Response Portal facilitates personalized medicine by linking genetic profiles to drug responses.

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