1259 Non-canonical NFκB kinase IKKα as a prognostic biomarker and potential therapeutic target for right-sided colon cancer

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McKenzie, Molly and Pennel, Kathryn and Lian, Guang-Yu and Santana, Leonor Schubert and Hatthakarnkul, Phimmada and Quinn, Jean and Legrini, Assya and Doncheva, Yoana and Wood, Colin and Lynch, Gerard P and Nixon, Colin and Powley, Ian and MacKay, Simon and Maka, Noori and Jamieson, Nigel and Edwards, Joanne (2025) 1259 Non-canonical NFκB kinase IKKα as a prognostic biomarker and potential therapeutic target for right-sided colon cancer. Journal for ImmunoTherapy of Cancer, 13 (Suppl ). A1434-A1435. ISSN 2051-1426 (https://doi.org/10.1136/jitc-2025-sitc2025.1259)

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Abstract

Background Right-sided colon cancer (CC) has poorer outcome compared to other disease sites1 and is unresponsive to current treatments.2 3 Inflammation has a well-established relationship within CC, such as through NFkB signalling;4 consisting of two distinct pathways, canonical and non-canonical, regulated by inhibitor of nuclear factor-kB kinase beta (IKKβ) and IKKα, respectively.5 As efforts to inhibit IKKβ have been unsuccessful,6 there is a need to examine if IKKα plays a prognostic role in right-sided CC, delineate the underlying signalling, and investigate if it can be targeted for therapeutic intervention. Methods TemO-SeqTM7 bulk transcriptomic analysis was performed on a cohort of 787 stage I-III CRC patients to examine differences between right- and left-sided CC, and immunohistochemistry (IHC) was used to validate the presence of inflammatory markers. Spatial transcriptomics, GeoMXTM Nanostring, was used to investigate the tumour microenvironments’ role. The results were validated at a protein-level using high-plex sequential immunofluorescence (20-plex) staining by COMETTM Lunaphore platform, together with the SPYRE Immuno-oncology core-panel kit. Patient derived explants (PDEs) were established8 and treated with 1mM fluorouracil (5FU) or 1mM SU1644. Tissue sections from PDE multiblocks were stained for Ki67 expression using IHC, and further 20-plex panels using the COMETTM Lunaphore platform. Results Right-sided CC patients had significantly activated Interferon-alpha/gamma and NFkB pathways at a transcriptomic level, when compared to left-sided disease (p<0.01). NFkB regulating kinases were assessed at a protein-level, where patients with IKKα high, IKKβ low expressing tumours had the poorest patient outcome (p=0.017) and this was heightened in right-sided disease (p<0.001), when compared to left and rectal cases (figure 1). Spatial transcriptomic GSEA results highlight enriched epithelial to mesenchymal transition (EMT) gene-sets across both the tumour and microenvironment of IKKa-high expressing patients (p<0.05). This was validated at protein-level, by analysing a 20-plex panel of EMT markers in PDE models, treated with a novel IKKa inhibitor SU1644 and standard of care chemotherapy 5FU (figure 2). Conclusions Results illustrate that right-sided CCs present with activated inflammatory signalling, and a central role of NFkB regulation. At a protein-level NFkB signalling, specifically IKKα driven regulation, is significantly associated with poor patient outcome and is heightened in right-sided disease. Across tissue compartments, EMT gene-sets are significantly enriched in these IKKa-high expressing patients. This can be targeted using SU1644, with results demonstrating a reduction in proliferation within a subset of colon tumours upon SU1644 treatment, a potential strategy to target metastasis in right-sided CC.

ORCID iDs

McKenzie, Molly, Pennel, Kathryn, Lian, Guang-Yu, Santana, Leonor Schubert, Hatthakarnkul, Phimmada, Quinn, Jean, Legrini, Assya, Doncheva, Yoana, Wood, Colin, Lynch, Gerard P, Nixon, Colin, Powley, Ian, MacKay, Simon ORCID logoORCID: https://orcid.org/0000-0001-8000-6557, Maka, Noori, Jamieson, Nigel and Edwards, Joanne;
CORE (COnnecting REpositories)