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Targeting the α4–α5 dimerization interface of K-RAS inhibits tumor formation in vivo

Oncogene volume 38, pages 2984–2993 (2019)Cite this article

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A Correction to this article was published on 01 February 2019

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Abstract

RAS genes are the most commonly mutated oncogenes in human cancers. Despite tremendous efforts over the past several decades, however, RAS-specific inhibitors remain elusive. Thus, targeting RAS remains a highly sought-after goal of cancer research. Previously, we have reported a new approach to inhibit RAS-dependent signaling and transformation in vitro by targeting the α4–α5 dimerization interface with a novel RAS-specific monobody termed NS1. Expression of NS1 inhibits oncogenic K-RAS and H-RAS signaling and transformation in vitro. Here, we evaluated the efficacy of targeting RAS dimerization as an approach to inhibit tumor formation in vivo. Using a doxycycline (DOX)-regulated NS1 expression system, we demonstrate that DOX-induced NS1 inhibited oncogenic K-RAS-driven tumor growth in vivo. Furthermore, we observed context-specific effects of NS1 on RAS-mediated signaling in 2D vs 3D growth conditions. Finally, our results highlight the potential therapeutic efficacy of targeting the α4–α5 dimerization interface as an approach to inhibit RAS-driven tumors in vivo.

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  • 01 February 2019

    Additionally, a further error has been corrected on page five in the sentence: Subsequent improvements to the chemistry of these lead compounds have resulted in the most recent interaction, with ARS-1620, which demonstrates selective inhibition of K-RAS(G12C) mutant tumor models in vivo [23]. The word ‘with’ has been removed from this sentence to ensure the correct meaning is communicated, such that the sentence now is: Subsequent improvements to the chemistry of these lead compounds have resulted in the most recent interaction, ARS-1620, which demonstrates selective inhibition of K-RAS(G12C) mutant tumor models in vivo [23].

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Acknowledgements

The authors wish to thank Drs. Andrei Karginov, Todd Waldman, Gregory Thatcher, Bernard Weisman, and Robert Winn for providing various cell lines. In addition, we wish to thank Drs. Shohei Koide and Andrei Karginov along with the O’Bryan and Karginov labs for many helpful discussions. R.S.S. was supported by an NIH F31 Predoctoral Award (CA192822). This work was supported in part by a Merit Review Award (1I01BX002095) from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service and NIH awards (CA212608 and CA201717) to J.P.O. The contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

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Author notes

  1. These authors contributed equally: Imran Khan and Russell Spencer-Smith

Authors and Affiliations

  1. Department of Pharmacology, University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Imran Khan, Russell Spencer-Smith & John P. O’Bryan

  2. Jesse Brown VA Medical Center, Chicago, IL, 60612, USA

    Imran Khan, Russell Spencer-Smith & John P. O’Bryan

  3. Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    Imran Khan & John P. O’Bryan

  4. Ralph H. Johnson VA Medical Center, Charleston, SC, 29401, USA

    Imran Khan & John P. O’Bryan

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  1. Imran Khan
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Correspondence to John P. O’Bryan.

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Khan, I., Spencer-Smith, R. & O’Bryan, J.P. Targeting the α4–α5 dimerization interface of K-RAS inhibits tumor formation in vivo. Oncogene 38, 2984–2993 (2019). https://doi.org/10.1038/s41388-018-0636-y

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