Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

Marica Rosaria Ippolito, Valentino Martis, Sara Martin, Andréa E. Tijhuis, Christy Hong, René Wardenaar, Marie Dumont, Johanna Zerbib, Diana C.J. Spierings, Daniele Fachinetti, Uri Ben-David, Floris Foijer, Stefano Santaguida*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed.

Original languageEnglish
Pages (from-to)2440-2454.e6
JournalDevelopmental Cell
Volume56
Issue number17
DOIs
StatePublished - 13 Sep 2021

Funding

FundersFunder number
Anna Obenauf and Christian Umkehrer
City of Paris
Devon Lukow and Jason Sheltzer
DoD CDMRPCA191148
Giuseppina De Feudis
Mike Hemann
Israel Cancer Research Fund
United States - Israel Binational Science Foundation2019228
Massachusetts Institute of Technology
Cold Spring Harbor Laboratory
Istituto Europeo di Oncologia
University of Manchester
Human Frontier Science Program
Fondazione Cariplo
Ministero della Salute5×1000
Ministero dell’Istruzione, dell’Università e della Ricerca
Israel Cancer Association20200111
KWF Kankerbestrijding2017-RUG-11457
Centre National de la Recherche Scientifique
Associazione Italiana per la Ricerca sul Cancro21665, GR-2018-12367077
Azrieli Foundation
Instituto Mexicano del Petróleo

    Keywords

    • aneuploidy
    • cancer
    • chemotherapy
    • drug resistance
    • genome instability

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