SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO

Patricia C. Borck, Isabella Boyle, Kristina Jankovic, Nolan Bick, Kyla Foster, Anthony C. Lau, Lucy I. Parker-Burns, Daniel A. Lubicki, Tianxia Li, Ashir A. Borah, Nicholas J. Lofaso, Sohani Sharma, Tessla Chan, Riya V. Kishen, Anisah Adeagbo, Srivatsan Raghavan, Elisa Aquilanti, John R. Prensner, J. Michael Krill-Burger, Todd R. Golub, Catarina D. Campbell, Joshua M. Dempster, Edmond M. Chan (emc2291@cumc.columbia.edu) and Francisca Vazquez (vazquez@broadinstitute.org)
Additional contact information
Patricia C. Borck: Broad Institute of MIT and Harvard
Isabella Boyle: Broad Institute of MIT and Harvard
Kristina Jankovic: Columbia University Irving Medical Center
Nolan Bick: Broad Institute of MIT and Harvard
Kyla Foster: Broad Institute of MIT and Harvard
Anthony C. Lau: Broad Institute of MIT and Harvard
Lucy I. Parker-Burns: Columbia University Irving Medical Center
Daniel A. Lubicki: Broad Institute of MIT and Harvard
Tianxia Li: Columbia University Irving Medical Center
Ashir A. Borah: Broad Institute of MIT and Harvard
Nicholas J. Lofaso: Columbia University Irving Medical Center
Sohani Sharma: Columbia University Irving Medical Center
Tessla Chan: Columbia University Irving Medical Center
Riya V. Kishen: Columbia University Irving Medical Center
Anisah Adeagbo: Broad Institute of MIT and Harvard
Srivatsan Raghavan: Broad Institute of MIT and Harvard
Elisa Aquilanti: Broad Institute of MIT and Harvard
John R. Prensner: Broad Institute of MIT and Harvard
J. Michael Krill-Burger: Broad Institute of MIT and Harvard
Todd R. Golub: Broad Institute of MIT and Harvard
Catarina D. Campbell: Broad Institute of MIT and Harvard
Joshua M. Dempster: Broad Institute of MIT and Harvard
Edmond M. Chan: Broad Institute of MIT and Harvard
Francisca Vazquez: Broad Institute of MIT and Harvard

Nature, 2025, vol. 638, issue 8052, 1104-1111

Abstract: Abstract Cancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets have been approved by the FDA or are in clinical trials, highlighting the potential of this approach1–3. Here we analysed large-scale CRISPR knockout screening data from the Cancer Dependency Map and identified a new synthetic lethal target, PELO, for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 or microsatellite instability-high (MSI-H). In 9p21.3-deleted cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD, a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required owing to MSI-H-associated mutations in TTC37 (also known as SKIC3), a critical component of the SKIc. We show that both cancer subtypes converge to destabilize the SKIc, which extracts mRNA from stalled ribosomes. In SKIc-deficient cells, PELO depletion induces the unfolded protein response, a stress response to accumulation of misfolded or unfolded nascent polypeptides. Together, our findings indicate PELO as a promising therapeutic target for a large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-08509-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:638:y:2025:i:8052:d:10.1038_s41586-024-08509-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-08509-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla (sonal.shukla@springer.com) and Springer Nature Abstracting and Indexing (indexing@springernature.com).