Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation

Paige E Solomon; Lisa L Kirkemo; Gary M Wilson; Kevin K Leung; Mark H Almond; Leanne C Sayles; E Alejandro Sweet-Cordero; Oren S Rosenberg; Joshua J Coon; James A Wells

doi:10.1016/j.mcpro.2022.100247

Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation

Mol Cell Proteomics. 2022 Jul;21(7):100247. doi: 10.1016/j.mcpro.2022.100247. Epub 2022 May 18.

Authors

Affiliations

¹ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
² Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
³ Division of Infectious Diseases, Department of Medicine, UCSF Medical Center, University of California, San Francisco, California, USA.
⁴ Department of Pediatrics, University of California San Francisco, California, USA.
⁵ Division of Infectious Diseases, Department of Medicine, UCSF Medical Center, University of California, San Francisco, California, USA; Department of Biophysics and Biochemistry, Chan Zuckerberg Biohub, San Francisco, California, USA.
⁶ Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA; National Center for Quantitative Biology of Complex Systems, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁷ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA. Electronic address: jim.wells@ucsf.edu.

Abstract

Since the discovery of oncogenes, there has been tremendous interest to understand their mechanistic basis and to develop broadly actionable therapeutics. Some of the most frequently activated oncogenes driving diverse cancers are c-MYC, EGFR, HER2, AKT, KRAS, BRAF, and MEK. Using a reductionist approach, we explored how cellular proteomes are remodeled in isogenic cell lines engineered with or without these driver oncogenes. The most striking discovery for all oncogenic models was the systematic downregulation of scores of antiviral proteins regulated by type 1 interferon. These findings extended to cancer cell lines and patient-derived xenograft models of highly refractory pancreatic cancer and osteosarcoma driven by KRAS and MYC oncogenes. The oncogenes reduced basal expression of and autocrine stimulation by type 1 interferon causing remarkable convergence on common phenotypic and functional profiles. In particular, there was dramatically lower expression of dsRNA sensors including DDX58 (RIG-I) and OAS proteins, which resulted in attenuated functional responses when the oncogenic cells were treated with the dsRNA mimetic, polyI:C, and increased susceptibility to infection with an RNA virus shown using SARS-CoV-2. Our reductionist approach provides molecular and functional insights connected to immune evasion hallmarks in cancers and suggests therapeutic opportunities.

Keywords: AKT; BRAF; EGFR; HER2; KRAS; MEK; MYC; double-stranded RNA; interferon; oncogenes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Restriction Factors
COVID-19* / immunology
Carcinogenesis
Cell Line, Tumor
Humans
Interferon-beta* / immunology
Oncogenes*
Proteomics*
Proto-Oncogene Proteins p21(ras) / genetics
SARS-CoV-2

Substances

Antiviral Restriction Factors
Interferon-beta
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding