Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage.

Humans DNA Damage Aneuploidy MAP Kinase Signaling System / drug effects Phthalazines / pharmacology Cell Line, Tumor Piperazines / pharmacology raf Kinases / metabolism Neoplasms / genetics CRISPR-Cas Systems Cell Line Proto-Oncogene Proteins c-raf / metabolism Drug Resistance, Neoplasm / genetics

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
09 Sep 2024

Historique:

received: 12 06 2024

accepted: 28 08 2024

medline: 10 9 2024

pubmed: 10 9 2024

entrez: 9 9 2024

Statut: epublish

Résumé

Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction. Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. We validate these results in human cancer cell lines. Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells.

Identifiants

DOI: 10.1038/s41467-024-52176-x PMID: 39251587

pubmed: 39251587

doi: 10.1038/s41467-024-52176-x

pii: 10.1038/s41467-024-52176-x

doi:

Substances chimiques

Phthalazines 0

olaparib WOH1JD9AR8

Piperazines 0

raf Kinases EC 2.7.11.1

Proto-Oncogene Proteins c-raf EC 2.7.11.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

7772

Subventions

Organisme : Israel Science Foundation (ISF)

ID : 1805/21

Organisme : Israel Cancer Research Fund (Israel Cancer Research Fund, Inc.)

ID : NA

Organisme : United States - Israel Binational Science Foundation (BSF)

ID : 2019228

Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)

ID : AIRC-MFAG 2018 - ID. 21665

Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)

ID : ERC-SyG-2020 951475

Informations de copyright

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