Harvard Medical School

Cancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets are FDA-approved or in clinical trials, highlighting the potential of this approach.1–3 Here, we analyzed large-scale CRISPR knockout screening data and identified a new synthetic lethal target, pelota mRNA surveillance and ribosome rescue factor (PELO), for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 (9p21.3-/-) or microsatellite instability-high (MSI-H). In 9p21.3-/- cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene focadhesin (FOCAD), a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required due to MSI-H-associated mutations in tetratricopeptide repeat domain 37 (TTC37), 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 (UPR), a stress response to accumulated misfolded or unfolded nascent polypeptides. Together, our findings nominate 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.