Extended Data Fig. 6: SKIc and PELO synthetic lethality in MSI-H cancers.
From: Synthetic lethality of mRNA quality control complexes in cancer
(a) PELO is a selective dependency in MSI-H cell lines. A panel of MSS (SW837, HT-29) and MSI-H (HCT-116, RKO, DLD1, MFE-319) cell lines after sgB2M (black) or sgPELO (blue). Data shown as mean ± s.e.m., n = 3 biologically independent replicates. (b) PELO DepMap Chronos dependency in MSI-H models as part of major MSI lineages. Models characterized by NGS MSI status, MSS (grey) or MSI-H (red). Two-tailed Students t-test of MSI to MSS by lineage; Bowel, P = 4.0 × 10−13; Uterine, P = 2.8 × 10−3; Overy, P = 2.0 × 10−3; Lymphoid, P = 0.03. (c) SKIc immunoblot in MSI and MSS models. Data is derived from one biological experiment. d) Correlation of SKIV2L and TTC37 relative protein levels from uterine cancer CPTAC proteomic data (n = 116). MSI-H tumors highlighted in red. Pearson’s coefficient of determination, R2 = 0.65. (e) Correlation of SKIV2L and TTC37 relative protein levels from colorectal CPTAC proteomic data (n = 96). MSI-H tumors highlighted in red. Pearson’s coefficient of determination, R2 = 0.52. (f) cBioPortal OncoPrint showing mutual exclusivity of FOCAD homozygous deletions, MSH2, PMS1, PMS2, RPL22 mutations across major lineage MSI-H solid tumors (bowel, uterine, endometrial). (g) PELO and WRN dependency comparison across MSI-H (n = 61) models by NGS grouped by TP53 LOF or WT status. PELO dependency score (blue), WRN (orange). Median denoted by red line. (h) Relative viability of DLD-1 MSI-H cells after sgPELO, sgWRN, and sgABCE1 on day 7. Data shown as mean ± s.e.m., n = 5 biologically independent replicates (i) Immunoblot validation of sgPELO and sgWRN knockout efficiency in experiments in (h), data presented is a single representative image from n = 2 biologically independent replicates.
