Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells

The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics. Kras is frequently mutated in lung cancer and two isoforms are generated via alternative splicing. Here, the authors show that the two isoforms have divergent roles in cancer stem cells and the main tumour cell population, which are regulated by hypoxia and endoplasmic reticulum stress.

Automated summary

The KRAS oncogene can generate two isoforms through alternative splicing, KRAS4A and KRAS4B. The splicing regulation of both isoforms is crucial for the development of Kras mutant tumors. KRAS4A is enriched in cancer stem-like cells and responds to hypoxia, while KRAS4B is induced by ER stress. Targeting KRAS4A splicing with existing drugs may be a potential therapeutic strategy for cancer treatment.