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

Author

Listed:
  • 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
    MIT Koch Institute for Integrative Cancer Research)

  • 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
    University of California San Francisco)

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.

Suggested Citation

  • 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 & Allan Balmain, 2021. "Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24498-7
    DOI: 10.1038/s41467-021-24498-7
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    Cited by:

    1. Miquel Anglada-Girotto & Ludovica Ciampi & Sophie Bonnal & Sarah A. Head & Samuel Miravet-Verde & Luis Serrano, 2024. "In silico RNA isoform screening to identify potential cancer driver exons with therapeutic applications," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Sébastien Campagne & Daniel Jutzi & Florian Malard & Maja Matoga & Ksenija Romane & Miki Feldmuller & Martino Colombo & Marc-David Ruepp & Frédéric H-T. Allain, 2023. "Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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