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Leveraging microenvironmental synthetic lethalities to treat cancer

Kevin J Metcalf1,2, Alaa Alazzeh2, Zena Werb2,3

  • 1Department of Surgery.

The Journal of Clinical Investigation
|March 15, 2021
PubMed

Insights

Synthetic lethality targets cancer vulnerabilities. Expanding this to the tumor microenvironment (TME) offers new strategies to overcome treatment resistance and improve cancer therapy outcomes.

Area of Science:

  • Oncology
  • Cancer Biology
  • Drug Discovery

Background:

  • Treatment resistance is a major cause of cancer mortality.
  • Synthetic lethality strategies targeting tumor cell mutations show promise but are insufficient alone.
  • Tumors evolve and resist treatment through interactions with the tumor microenvironment (TME).

Purpose of the Study:

  • To review the role of the TME in cancer treatment resistance.
  • To introduce the concept of contextual synthetic lethality.
  • To discuss therapeutic strategies leveraging TME synthetic lethality.

Main Methods:

  • Review of current scientific literature on the TME and synthetic lethality.
  • Analysis of the interplay between tumor cells and the TME in treatment resistance.
  • Synthesis of existing knowledge to propose novel therapeutic paradigms.

Main Results:

  • The TME dynamically influences tumor evolution and therapeutic resistance.
  • Targeting TME circuits offers a new approach beyond tumor cell-specific synthetic lethality.
  • Contextual synthetic lethality integrates tumor cell and TME vulnerabilities.

Conclusions:

  • The TME is a critical factor in cancer treatment resistance.
  • Expanding synthetic lethality to the TME (contextual synthetic lethality) is a promising strategy.
  • Leveraging TME synthetic lethality could significantly improve cancer therapy.

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