Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer

Abstract

Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy.

Identification of a 5-lncRNA-Based Signature for Immune Characteristics and Prognosis of Lung Squamous Cell Carcinoma and Verification of the Function of lncRNA SPATA41

“…High-risk patients may be more sensitive to chemotherapy of these drugs. A previous study reported that spliceosome-mediated RNA trans-splicing (SMaRT) could effectively overcome the obstacle that chemotherapy could not clear cancer cells with tumor specificity ( Woess et al, 2022 ). Their study could explain that the different chemoresistance between groups may be related to alternative splicing.…”

Investigating Cutaneous Squamous Cell Carcinoma in vitro and in vivo: Novel 3D Tools and Animal Models

“…Therefore, several laboratories work extensively for the establishment of both primary and metastatic cSCC cell lines ( 83 , 84 ). Furthermore, the use of the skin derived SCC cells assumes a significant meaning also in the context of those SCCs arising from a genetic condition, such as the RDEB (recessive dystrophic epidermolysis bullosa) where a targeted therapy approach is required ( 85 ).…”