Leveraging microenvironmental synthetic lethalities to treat cancer
Kevin J. Metcalf,1,2 Alaa Alazzeh,2 Zena Werb,2,3 and Valerie M. Weaver1,3,4,5
1Department of Surgery,
2Department of Anatomy,
3Helen Diller Family Comprehensive Cancer Center,
4Center for Bioengineering and Tissue Regeneration, and
5Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California, USA.
Address correspondence to: Valerie M. Weaver, Department of Surgery, Box 0456, HSE 560, University of California, 513 Parnassus Avenue, San Francisco, California 94143-0456, USA. Phone: 415.476.3826; Email: valerie.weaver@ucsf.edu.
Authorship note: ZW is deceased.
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1Department of Surgery,
2Department of Anatomy,
3Helen Diller Family Comprehensive Cancer Center,
4Center for Bioengineering and Tissue Regeneration, and
5Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California, USA.
Address correspondence to: Valerie M. Weaver, Department of Surgery, Box 0456, HSE 560, University of California, 513 Parnassus Avenue, San Francisco, California 94143-0456, USA. Phone: 415.476.3826; Email: valerie.weaver@ucsf.edu.
Authorship note: ZW is deceased.
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Alazzeh, A.
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1Department of Surgery,
2Department of Anatomy,
3Helen Diller Family Comprehensive Cancer Center,
4Center for Bioengineering and Tissue Regeneration, and
5Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California, USA.
Address correspondence to: Valerie M. Weaver, Department of Surgery, Box 0456, HSE 560, University of California, 513 Parnassus Avenue, San Francisco, California 94143-0456, USA. Phone: 415.476.3826; Email: valerie.weaver@ucsf.edu.
Authorship note: ZW is deceased.
Find articles by Werb, Z. in: JCI | PubMed | Google Scholar
1Department of Surgery,
2Department of Anatomy,
3Helen Diller Family Comprehensive Cancer Center,
4Center for Bioengineering and Tissue Regeneration, and
5Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California, USA.
Address correspondence to: Valerie M. Weaver, Department of Surgery, Box 0456, HSE 560, University of California, 513 Parnassus Avenue, San Francisco, California 94143-0456, USA. Phone: 415.476.3826; Email: valerie.weaver@ucsf.edu.
Authorship note: ZW is deceased.
Find articles by Weaver, V. in: JCI | PubMed | Google Scholar
Published March 15, 2021 - More info
J Clin Invest. 2021;131(6):e143765. https://doi.org/10.1172/JCI143765.
© 2021 American Society for Clinical Investigation
Treatment resistance leads to cancer patient mortality. Therapeutic approaches that employ synthetic lethality to target mutational vulnerabilities in key tumor cell signaling pathways have proven effective in overcoming therapeutic resistance in some cancers. Yet, tumors are organs composed of malignant cells residing within a cellular and noncellular stroma. Tumor evolution and resistance to anticancer treatment are mediated through a dynamic and reciprocal dialogue with the tumor microenvironment (TME). Accordingly, expanding tumor cell synthetic lethality to encompass contextual synthetic lethality has the potential to eradicate tumors by targeting critical TME circuits that promote tumor progression and therapeutic resistance. In this Review, we summarize current knowledge about the TME and discuss its role in treatment. We outline the concept of tumor cell–specific synthetic lethality and describe therapeutic approaches to expand this paradigm to leverage TME synthetic lethality to improve cancer therapy.
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