Targeting pan-essential genes in cancer: Challenges and opportunities

Liang Chang; Paloma Ruiz; Takahiro Ito; William R Sellers

doi:10.1016/j.ccell.2020.12.008

Targeting pan-essential genes in cancer: Challenges and opportunities

Cancer Cell. 2021 Apr 12;39(4):466-479. doi: 10.1016/j.ccell.2020.12.008. Epub 2021 Jan 14.

Authors

Liang Chang¹, Paloma Ruiz², Takahiro Ito³, William R Sellers⁴

Affiliations

¹ Broad Institute of Harvard and MIT, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Broad Institute of Harvard and MIT, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: wsellers@broadinstitute.org.

Abstract

Despite remarkable successes in the clinic, cancer targeted therapy development remains challenging and the failure rate is disappointingly high. This problem is partly due to the misapplication of the targeted therapy paradigm to therapeutics targeting pan-essential genes, which can result in therapeutics whereby efficacy is attenuated by dose-limiting toxicity. Here we summarize the key features of successful chemotherapy and targeted therapy agents, and use case studies to outline recurrent challenges to drug development efforts targeting pan-essential genes. Finally, we suggest strategies to avoid previous pitfalls for ongoing and future development of pan-essential therapeutics.

Keywords: drug development; pan-essential genes; target identification; target validation; targeted therapies.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Antineoplastic Agents / therapeutic use*
Drug Therapy
Genes, Essential / genetics*
Humans
Molecular Targeted Therapy* / methods
Neoplasms / genetics*
Neoplasms / therapy*
Treatment Outcome

Substances

Antineoplastic Agents

Grants and funding

R01 CA233626/CA/NCI NIH HHS/United States