RDEB (Recessive dystrophic epidermolysis bullosa) occurs due to skin collagen deficiency. It can be fatal due to the development of cSCC (cutaneous squamous cell carcinoma). The immune system cytokines called transforming growth factor-beta (TGFβ) can be useful in therapy. This study investigates the TGFβ signaling pathway and assesses its effects.

The researchers study the effects of both exogenous and endogenous TGFβ signaling. A panel of 11 RDEB patients with cSCC was the test subjects. Their primary tumor keratinocyte cell lines (SCCRDEBs) underwent testing. The tests assessed signaling and proliferation responses to exogenous TGFβ. Researchers studied the responses to TGFBR1 kinase inhibitors (SB‐431542 and AZ12601011 (AZA01)) by applying techniques like in vitro proliferation, clonogenicity, migration, 3D assays, and in vivo tumor xenograft assays.

All the SCCRDEBs responded to exogenous TGFβ by activating canonical SMAD signaling and proliferative arrest. The endogenous signaling got blocked by kinase inhibitors. This treatment inhibited SCCRDEBs proliferation, clonogenicity, migration, and invasion in 7, 6, 8, and 6 patients, respectively. But it promoted proliferation and clonogenicity in 2 patients. The in vitro cells with TGFBR1 addiction were treatable with SB-431542 inhibitor. It enhanced overall survival and reduced the tumor volume in subcutaneous xenografts. But, there was no effect on the non-addicted cells in this assay.

Therapeutic benefits in a majority of patients were due to TFGBR1 kinase activity targeting. But the cytokines’ tumor-suppressing potential is unclear. It will require biomarker identification to stratify patients before clinical therapy.

Ref: https://onlinelibrary.wiley.com/doi/10.1111/bjd.19421