A trojan horse to target spliceosome mutant cells

摘要

Spliceosomal mutations occur frequently in several cancer types. However, therapeutic drugs targeting mutant spliceosomal proteins are unavailable. In this study, North, Benbarche et at. engineered synthetic introns that were spliced specifically in cancer cells expressing the mutant spliceosome factor SF3B1. This led to expression of herpes simplex virus-thymidine kinase (HSV-TK) and vulnerability of cancer cells to treatment with the antiviral drug ganciclovir(GCV). Бhe authors determined endogenous introns that were spliced by mutant БF3B1 by analysing transcriptomes of tumour tissues from 271 patients with several types of cancer carrying SF3B1 mutations, compared with wild-type (WT) samples, and validated six selected introns in patient cohorts and cancer cell lines carrying a range of SF3B1 mutations. Based on these, the a uthors generated synthetic introns.