A novel combinatorial treatment for Neurofibromatosis type 1 tumours revealed through cross-species genetic analysis

Abstract Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder associated with a wide range of symptoms, including the formation of tumours along nerves. These tumours can affect nerve function, leading to pain and loss of sensory or motor capacity. Drug treatments are currently limited, and relatively few new targets have emerged for NF1 tumours despite intensive research. Therefore, new drugs to target NF1 -deficient tumour cells are urgently required. Here, we have used a cross-species screening strategy combined with bioinformatic analysis to identify candidates with a high chance of successful translation to humans. First, we used data from a synthetic lethal screen performed in Drosophila cells to identify novel drug targets of NF1 . Then, we performed statistical enrichment analysis of the screen results to identify further candidate targets that were not conserved between Drosophila and humans and could not have been found in the screen. We identified and validated hTERT as a synthetic lethal partner gene to NF1 with high potential as a therapeutic drug target, using the FDA-approved inhibitor azidothymidine (AZT). The lethal effect of AZT was validated in plexiform neurofibroma NF1 -deficient human cell lines and NF1 -deficient malignant peripheral nerve sheath tumour cells. The effect of AZT was also conserved in vivo, highlighting the translational potential; treatment of mice with AZT inhibited NF1 mutant xenograft growth to the same extent as the current clinically approved MEK inhibitor, selumetinib. Finally, we show that combined treatment with AZT and selumetinib resulted in a further synergistic reduction in NF1 -deficient human cell viability. In conclusion, AZT represents a promising novel therapeutic for the treatment of NF1 tumours, either alone or in combination with selumetinib.