Genome-wide screen for anticancer drug resistance in haploid human embryonic stem cells

Emanuel Segal, Jonathan Nissenbaum, Mordecai Peretz, Tamar Golan-Lev, Rivki Cashman, Hagit Philip, Benjamin E. Reubinoff, Oded Kopper, Nissim Benvenisty

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Anticancer drugs are at the frontline of cancer therapy. However, innate resistance to these drugs occurs in one-third to one-half of patients, exposing them to the side effects of these drugs with no meaningful benefit. To identify the genes and pathways that confer resistance to such therapies, we performed a genome-wide screen in haploid human embryonic stem cells (hESCs). These cells possess the advantage of having only one copy of each gene, harbour a normal karyotype, and lack any underlying point mutations. We initially show a close correlation between the potency of anticancer drugs in cancer cell lines to those in hESCs. We then exposed a genome-wide loss-of-function library of mutations in all protein-coding genes to 10 selected anticancer drugs, which represent five different mechanisms of drug therapies. The genetic screening enabled us to identify genes and pathways which can confer resistance to these drugs, demonstrating several common pathways. We validated a few of the resistance-conferring genes, demonstrating a significant shift in the effective drug concentrations to indicate a drug-specific effect to these genes. Strikingly, the p53 signalling pathway seems to induce resistance to a large array of anticancer drugs. The data shows dramatic effects of loss of p53 on resistance to many but not all drugs, calling for clinical evaluation of mutations in this gene prior to anticancer therapy.

Original languageEnglish
Article numbere13475
JournalCell Proliferation
Volume56
Issue number6
Early online date21 Apr 2023
DOIs
StatePublished - Jun 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.

Funding

We thank members of The Azrieli Center for Stem Cells and Genetic Research for critical reading of the manuscript. The results published or shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This work was partially supported by the Azrieli Foundation, the Israel Science Foundation (2054/22), the ISF-Israel Precision Medicine Partnership (IPMP) Program (3605/21) and by NewStem Ltd. Nissim Benvenisty is the Herbert Cohn Chair in Cancer Research. We thank members of The Azrieli Center for Stem Cells and Genetic Research for critical reading of the manuscript. The results published or shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga . This work was partially supported by the Azrieli Foundation, the Israel Science Foundation (2054/22), the ISF‐Israel Precision Medicine Partnership (IPMP) Program (3605/21) and by NewStem Ltd. Nissim Benvenisty is the Herbert Cohn Chair in Cancer Research.

FundersFunder number
ISF-Israel
NewStem LTD
Israel Science Foundation2054/22, 3605/21
Azrieli Foundation

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