Advancing a novel synthetic lethal target by exploiting ribosomal stress in Ch9p21.3-deleted or MSI-H cancers

Synthetic lethality (SL) offers a promising approach to selectively target cancers by exploiting their genome alterations not found in normal cells. Indeed, various inhibitors of SL drug targets are approved by the Food and Drug Administration or in clinical trials, highlighting the potential of such a therapeutic approach. Building on our success identifying (Chan et al. Nature 2019)1 and undercovering the molecular mechanisms (van Wietmarschen et al. Nature 2020)45 of WRN helicase as a SL target, we sought to identify additional SL cancer targets. As detailed in our recent publication (Borck et al. Nature 2025)8, we discovered Pelota (PELO) – HBS1-like translational GTPase (HBS1L) ribosome rescue complex (PELO-HBS1L) as a novel synthetic lethal target for two distinct and large molecular subtypes of cancers: biallelic chromosome 9p21.3 deletion (9p21.3-/-) and microsatellite instability (MSI-H). These independent molecular subtypes represent large classes of lethal cancers with an urgent need for novel therapies. We showed that that 9p21.3-/- mutations and MSI-H-related mutations independently destabilized the Super Killer complex (SKIc), which typically promotes the degradation of mRNA on stalled ribosomes. SKIc deficiency (dSKIc), by either mechanism, occurs in approximately 5% of all cancers and renders cells highly dependent on PELO for survival. These observations support the PELO-HBS1- Like Translational GTPase complex (PELO-HBS1L) as a SL target in dSKIc cancers with a promising path towards a novel class of precision oncology therapies. These findings also raise important mechanistic questions underlying this synthetic lethal phenomenon. In Aim 1, we will validate the hypothesis that dSKIc serves as a cancer-lineage agnostic predictor of PELO-HBS1L dependency by evaluating the viability effects of PELO knockdown and HBS1L knockdown in dSKIc and SKIc-proficient patient-derived organoid and in vivo xenograft models. In Aim 2, we will test the hypothesis that loss of PELO activity induces ribosome stalling and collisions in dSKIc cells. We will also evaluate whether the mRNAs that trigger a response from PELO are the same mRNAs that SKIc degrade, providing mechanistic insight into the interactions between SKIc and PELO. In Aim 3, we will dissect the downstream cellular consequences of PELO loss, building on our data demonstrating that PELO knockdown selectively activates the unfolded protein response (UPR), a marker of endoplasmic reticulum (ER) stress, in dSKIc cells. We will evaluate whether PELO knockdown induces accumulation of misfolded or unfolded proteins in the ER and whether UPR impairs dSKIc cell viability. Through these studies, we aim to firmly establish PELO and HBS1L as therapeutic targets for dSKIc cancers and elucidate the mechanisms underlying this SL relationship. These findings have immediate relevance by establishing fundamental understanding of dysregulated ribosomal homeostasis in cancers, catalyzing drug discovery efforts, and providing mechanistic insight to guide rational-based implementation of PELO-based therapeutics. Project Number: 1R01CA300313-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Edmond Chan | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $501,422 | Activity Code: R01 | Study Section: Gene Regulation in Cancer Study Section[GRIC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11297579