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Orcholski, M. E.

Publications and source records attributed to Orcholski, M. E..

2 recordsLinked to original sources
bioRxiv2026

CRISPR-enabled genetic screens identify synthetic lethal targets across frequently altered cancer drivers

Synthetic lethality (SL) provides a treatment paradigm for targeting cancer with alterations in driver genes that are not conventionally druggable, including loss-of-function (LoF) mutations in tumor suppressor genes and gain-of-function (GoF) alterations in oncogenes. We undertook a series of genome-wide CRISPR screens using functionally validated isogenic cell lines and also conducted a large-scale SL analysis using data from the cancer dependency map (DepMap). We charted SL interactions across 15 genetic alterations characteristic of diseases with high incidence and unmet clinical need: FBXW7, CCNE1, CDK12, ARID1A, KMT2D, DNMT3A, TET2, KEAP1, STK11, IDH1, SF3B1, SRSF2, U2AF1, chromosome 18q loss, and chromosome 13q loss. We show validation of several SL interactions between tractable targets with cancer drivers, including ARID1A and the hexosamine biosynthetic pathway aminotransferase GFPT1, STK11 with CAMK protein kinase family members including MARK2, FBXW7 and the CDK1 regulatory kinase PKMYT1, and CCNE1 amplification and the anaphase promoting complex or cyclosome (APC/C). In summary, this study offers a rich resource of genetic interactions across cancer drivers enabling the discovery of new biological insights and drug targets for future therapeutic development.

cancer biology↗
bioRxiv2026

Anticipating on-target resistance to WRN inhibitors in microsatellite unstable cancers

Leveraging WRN helicase dependency in microsatellite instability (MSI) cancers offers a synthetic lethal (SL) therapeutic opportunity, with several WRN inhibitors in development. However, the hypermutator nature of MSI tumors creates strong evolutionary pressure for rapid resistance. Here, we apply a multimodal functional genomics framework integrating base editing screens and deep mutational scanning to map on-target resistance to two clinical WRN inhibitors, HRO761 and VVD-214. We identify discrete resistance hotspots within WRN and demonstrate that single-allele (heterozygous) mutations at the drug-binding site are sufficient to abrogate WRN inhibitor-induced cytotoxicity. Resistance profiles diverged between HRO761 and VVD-214, revealing mutations that impair one but preserve sensitivity to the other. Genome-wide CRISPR screens further identified non-homologous end joining (NHEJ) factors and the checkpoint phosphatase WIP1 as tractable synthetic vulnerabilities that potentiate WRN inhibition. Together, these findings establish a framework for resistance-aware deployment of WRN inhibitors through rational drug selection, therapeutic switching, and combination strategies. Statement of SignificanceResistance to WRN inhibitors threatens the clinical durability of synthetic lethal therapies in microsatellite-instable cancers. Using multimodal functional genomics, we identify predictable, drug-specific on-target resistance mechanisms and reveal DNA-PK as a tractable combination partner. These findings provide a framework for resistance-aware deployment of WRN inhibitors to improve therapeutic durability.

cancer biology↗