Biology subjects

McCarten, K.

Publications and source records attributed to McCarten, K..

3 recordsLinked to original sources

bioRxiv2026

CRISPR-enhanced assessment of variants of unknown significance nominates oncology therapeutic targets and drug repositioning opportunities

Interpreting infrequent somatic variants remains a challenge in cancer genomics. We developed CRISPR-VUS, a framework that uses public Cancer Dependency Map data to identify Dependency-Associated Mutations (DAMs) - variants linked to increased host-gene dependency - with resolution extending to singleton events. Analysis of 977 cell lines across 36 cancer types identified 2,376 DAMs in 1,383 genes, including 1,260 not established as cancer drivers. DAM-bearing genes converge on oncogenic networks, while recurrence in histology-matched tumours, functional-impact predictions, tractability and pharmacological associations enable systematic prioritisation. Prime editing showed that the prioritised NSCLC-specific RTN4IP1-A80T DAM conferred a significant competitive growth advantage in a lung epithelial model, nominating a candidate driver allele. Exploratory pharmacological testing showed a greater maximal response to istaroxime in ATP1B3-I189M-bearing than in ATP1B3-wild-type cells. CRISPR-VUS combines dependency-based rare-variant discovery with evidence-guided prioritisation to nominate candidate drivers, therapeutic targets and drug-repositioning hypotheses. Interactive results are available at https://vus-portal.fht.org/.

bioinformatics↗

bioRxiv2025

On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells.

Werner helicase inhibitors (WRNi) are in clinical development for microsatellite-unstable (MSI) tumors with defective DNA mismatch repair. Here, we investigate how cancer cell evolution shapes response to WRN inhibition and informs potential resistance mechanisms. Genome-wide CRISPR screens combined with WRN knockout did not identify bypass mechanisms, underscoring WRNs essential, non-redundant function in MSI cells. Pharmacogenomic screens identified modulators of WRNi sensitivity, including SMARCAL1, which links it to WRN-MSI synthetic lethality. Semi-saturation mutagenesis of WRN and prolonged drug treatment identified on-target WRN mutations driving acquired resistance to multiple WRNi in vitro and in vivo, which was mitigated by combination with standard chemotherapies. Some resistance mutations conferred broad cross-resistance, whereas others preserved sensitivity to alternative clinical-grade WRNi with distinct mechanism of action. Our findings could inform clinical trial design by suggesting the feasibility of real-time tracking of emerging resistance and enabling early therapeutic adaptations. SignificanceWe present the first exploration of how MSI cancer cells evolve under the selective pressure of WRN helicase inhibition, providing a framework for understanding adaptive responses to this newly identified synthetic-lethal dependency. This study identifies on-target WRN mutations as key drivers of resistance in MSI cancers, supporting the use of combination strategies with other standard-of-care treatments to prevent resistance. It highlights how mutation tracking can guide therapeutic switching to clinically available WRN inhibitors with distinct mechanisms of action, thereby refining clinical development and potentially improving biomarker-informed patient outcomes.

cancer biology↗

bioRxiv2022

Elevated FOXG1 supports exit from quiescence in neural stem cells through FoxO6

The molecular mechanisms controlling the balance of quiescence and proliferation in adult neural stem cells (NSCs) are often deregulated in brain cancers such as glioblastoma (GBM). Previously, we reported that FOXG1, a forebrain-restricted neurodevelopmental transcription factor, is frequently upregulated in glioblastoma stem cells (GSCs) and limits the effects of cytostatic pathways, in part by repression of the tumour suppressor Foxo3. Here, we show that increased FOXG1 upregulates FoxO6, a more recently discovered FoxO family member with potential oncogenic functions. Although genetic ablation of FoxO6 in proliferating NSCs has no effect on the cell cycle or entry into quiescence, we find that FoxO6-null NSCs can no longer efficiently exit quiescence following FOXG1 elevation. Increased FoxO6 results in the formation of large acidic vacuoles, reminiscent of Pak1-regulated macropinocytosis. Consistently, Pak1 expression is upregulated by FOXG1 overexpression and downregulated upon FoxO6 loss in proliferative NSCs. These data suggest a pro-oncogenic role for FoxO6 in controlling the exit from quiescence in NSCs, and shed light on the functions of this underexplored FoxO family member. Research highlightsO_LIFoxO6 is a downstream effector of elevated FOXG1 in mouse NSCs and GSCs. C_LIO_LIUpregulation of FoxO6 is necessary for FOXG1 to drive efficient quiescence exit of NSCs. C_LIO_LIFoxO6 overexpression stimulates macropinocytosis, a process regulated by the actin cytoskeleton regulator Pak1. C_LIO_LIPak1 is upregulated by FOXG1 overexpression and downregulated upon FoxO6 loss. C_LI

cancer biology↗