Targeting the transcription cycle and RNA processing in cancer treatment.

Abstract

The transcriptional program and RNA splicing machinery are highly and frequently dysregulated in human cancers due to genomic and epigenomic alterations during tumorigenesis. This leads to cancer-specific dependencies on components of the transcriptional program and RNA splicing machinery, providing alternative and targetable Achilles heels for cancer treatment in the clinic. To target these vulnerabilities in cancer cells, potent and specific transcriptional CDK inhibitors and chemical compounds that impair splicing have been developed and evaluated in preclinical cancer models. Several novel combination approaches with immune or targeted therapies have also been proposed for cancer treatment. More recently, inhibitors targeting transcriptional CDKs, splicing, or PRMT5 have shown promising therapeutic potential in preclinical studies, and many of them have rapidly advanced into early clinical trials for treatment of human cancer.