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

Wei-Ching Chen, Minh D. To, Peter M. K. Westcott, Reyno Delrosario, Il-Jin Kim, Mark Philips, Quan Tran, Saumya R. Bollam, Hani Goodarzi, Nora Bayani, Olga Mirzoeva and Allan Balmain ()
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Wei-Ching Chen: UCSF Helen Diller Family Comprehensive Cancer Center
Minh D. To: UCSF Helen Diller Family Comprehensive Cancer Center
Peter M. K. Westcott: UCSF Helen Diller Family Comprehensive Cancer Center
Reyno Delrosario: UCSF Helen Diller Family Comprehensive Cancer Center
Il-Jin Kim: Guardant Health
Mark Philips: NYU Cancer Institute, NYU School of Medicine
Quan Tran: UCSF Helen Diller Family Comprehensive Cancer Center
Saumya R. Bollam: UCSF Helen Diller Family Comprehensive Cancer Center
Hani Goodarzi: University of California San Francisco
Nora Bayani: UCSF Helen Diller Family Comprehensive Cancer Center
Olga Mirzoeva: UCSF Helen Diller Family Comprehensive Cancer Center
Allan Balmain: UCSF Helen Diller Family Comprehensive Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24498-7

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