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Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human

Sonam Dolma1, Stephen L Lessnick, William C Hahn

  • 1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.

Cancer Cell
|April 5, 2003
PubMed

Insights

Synthetic lethal screening identified compounds selectively killing cancer cells. These drugs show enhanced activity with specific oncoproteins and oncogenes, revealing new cancer vulnerabilities.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cancer cells often harbor genetic alterations not present in normal cells.
  • Synthetic lethality offers a strategy to selectively target cancer cells.
  • High-throughput screening (HTS) enables rapid evaluation of large compound libraries.

Purpose of the Study:

  • To identify compounds exhibiting genotype-selective cytotoxicity against engineered tumorigenic cells.
  • To investigate the influence of specific oncoproteins and oncogenes on compound activity.
  • To discover novel compounds with potential therapeutic applications in cancer.

Main Methods:

  • Conducted a synthetic lethal high-throughput screen of 23,550 compounds.
  • Utilized engineered tumorigenic and isogenic normal cell lines.
  • Assessed compound activity in the presence of specific oncoproteins (hTERT, SV40 T oncoproteins, HPV E6/E7) and oncogenes (HRAS).

Main Results:

  • Identified known (doxorubicin, daunorubicin, etc.) and novel compounds (erastin) with genotype-selective activity.
  • Observed increased compound efficacy in cells overexpressing hTERT, SV40 T oncoproteins, HPV oncoproteins, and HRAS.
  • Found that specific oncoprotein/oncogene combinations modulated topoisomerase expression and sensitized cells to erastin-induced non-apoptotic cell death.

Conclusions:

  • Synthetic lethal screening is effective in discovering genotype-selective anti-cancer compounds.
  • Specific oncoproteins and oncogenes can enhance the activity of certain chemotherapeutics.
  • The identified compounds and mechanisms provide new avenues for targeted cancer therapy development.

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