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

Johanna Zerbib, Marica Rosaria Ippolito, Yonatan Eliezer, Giuseppina Feudis, Eli Reuveni, Anouk Savir Kadmon, Sara Martin, Sonia Viganò, Gil Leor, James Berstler, Julia Muenzner, Michael Mülleder, Emma M. Campagnolo, Eldad D. Shulman, Tiangen Chang, Carmela Rubolino, Kathrin Laue, Yael Cohen-Sharir, Simone Scorzoni, Silvia Taglietti, Alice Ratti, Chani Stossel, Talia Golan, Francesco Nicassio, Eytan Ruppin, Markus Ralser, Francisca Vazquez, Uri Ben-David () and Stefano Santaguida ()
Additional contact information
Johanna Zerbib: Tel Aviv University
Marica Rosaria Ippolito: European Institute of Oncology IRCCS
Yonatan Eliezer: Tel Aviv University
Giuseppina Feudis: European Institute of Oncology IRCCS
Eli Reuveni: Tel Aviv University
Anouk Savir Kadmon: Tel Aviv University
Sara Martin: European Institute of Oncology IRCCS
Sonia Viganò: European Institute of Oncology IRCCS
Gil Leor: Tel Aviv University
James Berstler: Broad Institute of MIT and Harvard
Julia Muenzner: Department of Biochemistry
Michael Mülleder: Core Facility High-Throughput Mass Spectrometry
Emma M. Campagnolo: National Cancer Institute, National Institutes of Health
Eldad D. Shulman: National Cancer Institute, National Institutes of Health
Tiangen Chang: National Cancer Institute, National Institutes of Health
Carmela Rubolino: Fondazione Instituto Italiano di Technologia
Kathrin Laue: Tel Aviv University
Yael Cohen-Sharir: Tel Aviv University
Simone Scorzoni: European Institute of Oncology IRCCS
Silvia Taglietti: European Institute of Oncology IRCCS
Alice Ratti: European Institute of Oncology IRCCS
Chani Stossel: Sheba Medical Center
Talia Golan: Sheba Medical Center
Francesco Nicassio: Fondazione Instituto Italiano di Technologia
Eytan Ruppin: National Cancer Institute, National Institutes of Health
Markus Ralser: Department of Biochemistry
Francisca Vazquez: Broad Institute of MIT and Harvard
Uri Ben-David: Tel Aviv University
Stefano Santaguida: European Institute of Oncology IRCCS

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52176-x

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