Abstract
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.
Highlights
The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing
Expression of Kras4A and Kras4B isoforms in normal tissues from these mice showed the expected patterns (Supplementary Fig. 1), and mouse embryonic fibroblasts (MEFs) isolated from E13.5 embryos showed robust EGF-induced activation of MapK and Akt, indicating that Kras4A and Kras4B are both activated in response to EGF in cells that lack the alternative isoform (Supplementary Fig. 2)
Since our mouse genetic data suggested that controlled expression of both Kras4A and Kras4B isoforms from the same allele is necessary for tumor formation, we explored the possibility that small molecule inhibitors of different components of the splice site machinery may impact growth of KRAS mutant tumour cells[9,10]
Summary
The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. It has previously been demonstrated that mice lacking only the Kras4A isoform are resistant to chemically induced lung cancer[6,7], in spite of the fact that Kras4A is expressed only in a subpopulation of normal and tumor cells These data led to the proposal that Kras4A plays an essential role in tumor development, possibly through effects on a minor stem cell population[6]. We design a genetic approach to investigate the distinct functions of Kras4A and Kras4B in mouse models and human cancers This analysis shows that each isoform is individually dispensable for normal mouse development, but that expression of both splice isoforms from the same Kras allele is required for initiation and growth of Kras mutant cancers. Since KRAS4A is enriched in a sub-population of cells with stem cell properties, our data suggest a model in which coordination of the stemprogenitor cell transition in cancers may be achieved through regulation of KRAS mRNA splicing, identifying a potential vulnerability in KRAS mutant tumors
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
