Oxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies
Adedeji K. Adebayo,
Poornima Bhat-Nakshatri,
Christopher Davis,
Steven P. Angus,
Cihat Erdogan,
Hongyu Gao,
Nick Green,
Brijesh Kumar,
Yunlong Liu,
Harikrishna Nakshatri
Affiliations
Adedeji K. Adebayo
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Poornima Bhat-Nakshatri
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Christopher Davis
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Steven P. Angus
Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Cihat Erdogan
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Hongyu Gao
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Nick Green
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Brijesh Kumar
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Yunlong Liu
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Harikrishna Nakshatri
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Roudebush VA Medical Center, Indianapolis, IN 46202, USA; Corresponding author
Summary: Most cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air. This aided comparison of baseline and drug-induced changes in signaling pathways under physioxia and ambient oxygen. Using tumor cells from transgenic models of breast cancer and cells from breast tissues of clinically breast cancer-free women, we demonstrate oxygen-dependent differences in cell preference for epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor beta (PDGFRβ) signaling. Physioxia caused PDGFRβ-mediated activation of AKT and extracellular regulated kinase (ERK) that reduced sensitivity to EGFR and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibition and maintained PDGFRβ+ epithelial-mesenchymal hybrid cells with potential cancer stem cell (CSC) properties. Cells in ambient air displayed differential EGFR activation and were more sensitive to targeted therapies. Our data emphasize the importance of oxygen considerations in preclinical cancer research to identify effective drug targets and develop combination therapy regimens.
