Background: Recessive dystrophic epidermolysis bullosa (RDEB) is associated with a high mortality rate due to the development of life threatening, metastatic cutaneous squamous cell carcinoma (cSCC). Elevated transforming growth factor β (TGFβ) signalling is implicated in cSCC development and progression in RDEB patients.
Objective: To determine the effect of exogenous and endogenous TGFβ signalling in RDEB cSCC with a view to assess the potential of targeting TGFβ signalling for RDEB cSCC therapy.
Methods: A panel of 11 patient derived RDEB cSCC primary tumour keratinocyte cell lines (SCCRDEBs) were tested for their signalling and proliferation responses to exogenous TGFβ. Their responses to TGFBR1 kinase inhibitors (SB-431542 and AZ12601011(AZA01)) was tested using in vitro proliferation, clonogenicity, migration, 3D invasion assays and in vivo tumour xenograft assays.
Results: All SCCRDEBs respond to exogenous TGFβ by activation of canonical SMAD signalling and proliferative arrest. Blocking endogenous signalling by treatment with SB-431542 and AZ12601011 significantly inhibited proliferation (n=7/11), clonogenicity (n=6/11), migration (n=8/11) and invasion (6/11) of SCCRDEBs. However, these TGFBR1 kinase inhibitors also promoted proliferation and clonogenicity in 2/11 SCCRDEBs. Pre-treatment of in vitro TGFBR1 addicted SCCRDEB70 cells with SB-431542 enhanced overall survival and reduced tumour volume in subcutaneous xenografts but had no effect on non-addicted SCCRDEB2 cells in these assays.
Conclusion: Targeting TGFBR1 kinase activity may have therapeutic benefit in the majority of RDEB cSCCs, however, the potential tumour suppressive role of TGFβ signalling in a subset of RDEB cSCCs necessitates biomarker identification to enable patient stratification before clinical intervention.