Episode 38 - Non canonical NF-κB signalling in CYLD cutaneous syndrome

In this episode of BJD Talks, Sam and Meera discuss the article ‘Targeting noncanonical nuclear factor kappa B signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha’ by Hodgson et al. The full article can be accessed at https://doi.org/10.1093/bjd/ljag044

*This podcast was generated by an AI tool created by 67Bricks for the British Association of Dermatologists*

Transcript

Sam: Welcome to BJD Talks, the official podcast of the BJD. I'm Sam.

Meera: And I'm Meera. In this episode, we will be discussing the article by Kirsty Hodgson and Joe Inns from the Rajan lab., "Targeting noncanonical nuclear factor kappa B signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha,” from March 2026 and included in the June 2026 issue.

Sam: Meera, this study is fascinating, especially as it tackles CYLD Cutaneous Syndrome—a challenging and often overlooked genetic condition. Shall we start with the basics for our listeners? What is CYLD Cutaneous Syndrome, or CCS?

Meera: Certainly. CCS is a rare, inherited skin condition caused by pathogenic variants in the CYLD gene, which typically acts as a tumour suppressor. When mutated, it leads to uncontrolled activation of the NF-kappa B pathway. This causes benign skin tumours—cylindromas and spiradenomas—which can grow in large numbers, especially on the scalp, face, and torso. Often, these tumours require repeated surgical removal, and in extreme cases, even scalp removal.

Sam: I imagine these surgeries aren't just physically demanding but take a huge emotional toll as well.

Meera: Exactly, and this is what makes the study so significant. The Rajan Lab focused on the noncanonical NF-kappa B signalling pathway, overactive in CCS. The key discovery here is identifying IκB kinase alpha, or IKK alpha, as a major player in the pathway and a potential therapeutic target.

Sam: They employed quite a methodology, didn’t they? Patient-derived tumour spheroid models combined with transcriptomic and proteomic analyses. What should we make of this approach?

Meera: Yes, it’s a sophisticated approach. Using patient-derived tumour cell fractions, they studied how noncanonical NF-kappa B signalling drives tumour growth. They then tested SU1644, a highly selective IKK alpha inhibitor, on these tumour spheroids. Without access to an animal model for CCS, this setup successfully mimicked the tumour environment.

Sam: And the results? Did SU1644 demonstrate efficacy in reducing tumour cell viability?

Meera: It did. SU1644 significantly reduced the viability of tumour spheroids. It also lowered levels of the protein p100 and its processed form p52, which are indicative of overactive noncanonical signalling. Intriguingly, it reduced truncated CYLD expression as well, suggesting it could address some underlying drivers of the disease.

Sam: That’s remarkable—both targeting the tumours and the pathway fuelling them. But what limitations did the study face?

Meera: The main challenges include the lack of a reliable animal model, so we don’t yet know how these therapies would perform in a living organism. Translating these findings into a patient-ready treatment, such as a topical formulation, will also require further research and clinical trials.

Sam: A topical treatment would indeed be transformative for CCS patients, providing a non-invasive alternative to invasive surgeries.

Meera: Absolutely. A topical IKK alpha inhibitor could offer a preventive option, especially for early-stage or at-risk patients. It’s precisely the sort of innovation dermatology strives to achieve.

Sam: In conclusion, this study introduces a promising strategy for tackling CCS by targeting IKK alpha in the noncanonical NF-kappa B pathway. SU1644 has shown great preclinical potential, and with further research, it may potentially reduce surgical interventions and improve patients' quality of life.

Meera: Perfectly summed up, Sam. It’s exciting to think of the hope this research brings to CCS patients. Well done to members of the Rajan Lab and their wide range of collaborators for their outstanding contributions.

Sam: And thank you, Meera, for guiding us through this impactful study. To our listeners, join us next time on BJD Talks for more insights.