Rescuing nonsense in cancer: recovering p53 tumor suppressor gene expression by translational readthrough inducing drugs (TRIDs)

Abstract

Mutation-based treatments represent a burgeoning frontier in genetic medicine, wherein therapeutic interventions are tailored according to the specific mutation profile of a patient. Recently, considerable attention has been directed towards addressing diseases stemming from premature termination codons (PTCs). A novel class of drugs, known as Translational readthrough-inducing drugs (TRIDs), has emerged with the capacity to facilitate the readthrough of PTCs, thereby reinstating the synthesis of full-length functional proteins. This study focuses on the potential of three newly synthesized TRIDs: NV848, NV914, and NV930, in promoting the production of functional p53 protein from a cDNA sequence carrying a PTC. The investigation involved the treatment of a human cancer cell line (H1299-p53R213X) engineered to harbor a PTC, where significant levels of readthrough were achieved upon treatment with the aforementioned TRIDs. After 24 hours of treatment with TRID molecules, we analyzed the expression of the p53 mRNA by real-time RT-PCR, observing that the treatment induces the stabilization of mutant p53 mRNA, resulting in augmented protein expression that appears functional. The observed upregulation of p53-target genes, after DNA damage induction by Doxorubicin, further corroborated these findings. These results herald a promising avenue for the development of targeted cancer therapies tailored to address nonsense mutations within tumor suppressor genes. They underscore the feasibility of employing molecules designed to induce stop-codon readthrough as a way to impede tumor proliferation. Moreover, they furnish a rational groundwork for the formulation of novel personalized treatment modalities, thereby enriching the existing repertoire of cancer therapeutics.