How Driver Oncogenes Shape and Are Shaped by Alternative Splicing Mechanisms in Tumors

The development of RNA sequencing methods has allowed us to study and better understand the landscape of aberrant pre-mRNA splicing in tumors. Altered splicing patterns are observed in many different tumors and affect all hallmarks of cancer: growth signal independence, avoidance of apoptosis, unlimited proliferation, invasiveness, angiogenesis, and metabolism. In this review, we focus on the interplay between driver oncogenes and alternative splicing in cancer. On one hand, oncogenic proteins-mutant p53, CMYC, KRAS, or PI3K-modify the alternative splicing landscape by regulating expression, phosphorylation, and interaction of splicing factors with spliceosome components. Some splicing factors-SRSF1 and hnRNPA1-are also driver oncogenes. At the same time, aberrant splicing activates key oncogenes and oncogenic pathways: p53 oncogenic isoforms, the RAS-RAF-MAPK pathway, the PI3K-mTOR pathway, the EGF and FGF receptor families, and SRSF1 splicing factor. The ultimate goal of cancer research is a better diagnosis and treatment of cancer patients. In the final part of this review, we discuss present therapeutic opportunities and possible directions of further studies aiming to design therapies targeting alternative splicing mechanisms in the context of driver oncogenes.

Automated summary

The development of RNA sequencing methods enables us to study and understand the aberrant pre-mRNA splicing in tumors. Altered splicing patterns affect various aspects of cancer development and are influenced by driver oncogenes. In turn, aberrant splicing activates key oncogenes and oncogenic pathways. Cancer research aims to improve diagnosis and treatment, and targeting alternative splicing mechanisms in the context of driver oncogenes presents potential therapeutic opportunities.