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Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer

  • Jorien B.E. Janssen
    Affiliations
    Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Medical Oncology, Nijmegen, the Netherlands
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  • Jan Paul Medema
    Affiliations
    Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam, the Netherlands
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  • Elske C. Gootjes
    Affiliations
    Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Medical Oncology, Nijmegen, the Netherlands
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  • Author Footnotes
    1 Shared last author.
    Daniele V.F. Tauriello
    Correspondence
    Corresponding authors at: Department of Medical Oncology, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525GA Nijmegen, the Netherlands.
    Footnotes
    1 Shared last author.
    Affiliations
    Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Cell Biology, Nijmegen, the Netherlands
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  • Author Footnotes
    1 Shared last author.
    Henk M.W. Verheul
    Correspondence
    Corresponding authors at: Department of Medical Oncology, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6525GA Nijmegen, the Netherlands.
    Footnotes
    1 Shared last author.
    Affiliations
    Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Medical Oncology, Nijmegen, the Netherlands
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  • Author Footnotes
    1 Shared last author.

      Highlights

      • RAS mutations occur in roughly half of the patients with colorectal cancer (CRC).
      • Oncogenic RAS induces a pro-metastatic immunosuppressive tumor microenvironment.
      • This suppressive environment prevents effective anti-tumor immune responses.
      • Effective treatments tailored to KRAS mutant metastatic CRC are needed.
      • Focus should be on combinations of immunotherapy with RAS-targeted treatments.

      Abstract

      RAS genes are the most frequently mutated oncogenes in cancer. These mutations occur in roughly half of the patients with colorectal cancer (CRC). RAS mutant tumors are resistant to therapy with anti-EGFR monoclonal antibodies. Therefore, patients with RAS mutant CRC currently have few effective therapy options. RAS mutations lead to constitutively active RAS GTPases, involved in multiple downstream signaling pathways. These alterations are associated with a tumor microenvironment (TME) that drives immune evasion and disease progression by mechanisms that remain incompletely understood. In this review, we focus on the available evidence in the literature explaining the potential effects of RAS mutations on the CRC microenvironment. Ongoing efforts to influence the TME by targeting mutant RAS and thereby sensitizing these tumors to immunotherapy will be discussed as well.

      Keywords

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