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KRas plays a negative role in regulating IDO1 expression

Xiandong Peng1, Eunji Lee1, Jialu Liang1

  • 1Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA.

Translational Oncology
|November 17, 2024
PubMed

Insights

Ras signaling negatively regulates Indoleamine 2,3-dioxygenase-1 (IDO1) expression while promoting Programmed cell death protein 1 ligand 1 (PD-L1) expression in KRas-mutant cancers. Inhibiting KRasG12C increases IDO1, suggesting combined KRas and IDO1 targeting for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Ras proteins are crucial signaling mediators involved in cellular processes, with mutations linked to cancer and inflammatory diseases.
  • Immune checkpoint proteins (PD-1/PD-L1) and IDO1 are key players in tumor immune evasion.
  • The role of KRas in regulating IDO1 expression is not well understood, unlike its established effect on PD-L1.

Purpose of the Study:

  • To investigate the differential regulation of IDO1 and PD-L1 in KRas-mutant cancers.
  • To elucidate the impact of KRas signaling on IDO1 expression.
  • To explore the therapeutic potential of targeting KRas and IDO1 concurrently.

Main Methods:

  • Analysis of IDO1 and PD-L1 expression in KRas-mutant cancer cell lines and patient samples.
  • Treatment of KRasG12C-mutant cells with the specific inhibitor ARS-1620.
  • Investigation of Interferon-gamma (IFN-γ) induced IDO1 expression in the presence of active KRas.
  • Assessment of the involvement of the MAPK pathway in KRas inhibition-induced IDO1 expression.

Main Results:

  • IDO1 and PD-L1 are differentially regulated in KRas-mutant cancers.
  • KRasG12C inhibition by ARS-1620 increased IDO1 expression, inversely correlating with PD-L1 levels in H358 cells.
  • IDO1 expression was reduced in lung and pancreatic ductal adenocarcinoma patients with KRas mutations.
  • Constitutively active KRas attenuated IFN-γ-induced IDO1 expression.
  • KRas inhibition-induced IDO1 expression occurred independently of the MAPK pathway.

Conclusions:

  • KRas signaling negatively regulates IDO1 expression and positively regulates PD-L1 expression.
  • KRas inhibition can restore IDO1 expression, suggesting a potential therapeutic strategy.
  • Concurrent targeting of KRas and IDO1 may enhance treatment efficacy and overcome resistance to immune checkpoint blockade in KRas-mutant cancers.
Keywords:
IDO1Immune checkpointInterferon-rKRasPD-L1

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