Synthetic lethality of mRNA quality control complexes in cancer

Vivian Prindle, Adam E. Richardson, Kimberly R. Sher, Sarah Kongpachith, Kaitlin Kentala, Sakina Petiwala, Dong Cheng, Deborah Widomski, Phuong Le, Maricel Torrent, Anlu Chen, Stephen Walker, Marianne B. Palczewski, Diya Mitra, Vlasios Manaves, Xu Shi, Charles Lu, Stephanie Sandoval, Zoltan Dezso, F. Gregory Buchanan, Daniel Verduzco, Brian Bierie, Jonathan A. Meulbroek, William N. Pappano and Joshua P. Plotnik ()
Additional contact information
Vivian Prindle: AbbVie
Adam E. Richardson: AbbVie
Kimberly R. Sher: AbbVie
Sarah Kongpachith: AbbVie Bay Area
Kaitlin Kentala: AbbVie
Sakina Petiwala: AbbVie
Dong Cheng: AbbVie
Deborah Widomski: AbbVie
Phuong Le: AbbVie
Maricel Torrent: AbbVie
Anlu Chen: AbbVie Bay Area
Stephen Walker: AbbVie
Marianne B. Palczewski: AbbVie
Diya Mitra: AbbVie
Vlasios Manaves: AbbVie
Xu Shi: AbbVie Bay Area
Charles Lu: AbbVie
Stephanie Sandoval: AbbVie
Zoltan Dezso: AbbVie Bay Area
F. Gregory Buchanan: AbbVie
Daniel Verduzco: AbbVie
Brian Bierie: AbbVie
Jonathan A. Meulbroek: AbbVie
William N. Pappano: AbbVie
Joshua P. Plotnik: AbbVie

Nature, 2025, vol. 638, issue 8052, 1095-1103

Abstract: Abstract Synthetic lethality exploits the genetic vulnerabilities of cancer cells to enable a targeted, precision approach to treat cancer1. Over the past 15 years, synthetic lethal cancer target discovery approaches have led to clinical successes of PARP inhibitors2 and ushered several next-generation therapeutic targets such as WRN3, USP14, PKMYT15, POLQ6 and PRMT57 into the clinic. Here we identify, in human cancer, a novel synthetic lethal interaction between the PELO–HBS1L and SKI complexes of the mRNA quality control pathway. In distinct genetic contexts, including 9p21.3-deleted and high microsatellite instability (MSI-H) tumours, we found that phenotypically destabilized SKI complex leads to dependence on the PELO–HBS1L ribosomal rescue complex. PELO–HBS1L and SKI complex synthetic lethality alters the normal cell cycle and drives the unfolded protein response through the activation of IRE1, as well as robust tumour growth inhibition. Our results indicate that PELO and HBS1L represent novel therapeutic targets whose dependence converges upon SKI complex destabilization, a common phenotypic biomarker in diverse genetic contexts representing a significant population of patients with cancer.

Date: 2025
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DOI: 10.1038/s41586-024-08398-6

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