Oxygen Tension-dependent Variability in the Cancer Cell Kinome Impacts Signaling Pathways and Response to Targeted Therapies

Overview

Journal iScience

Publisher Cell Press

Date 2024 Jun 14

PMID 38872973

Authors

Adedeji K Adebayo

Poornima Bhat-Nakshatri

Christopher Davis

Steven P Angus

Cihat Erdogan

Hongyu Gao

Nick Green

Brijesh Kumar

Yunlong Liu

Harikrishna Nakshatri

Affiliations

Soon will be listed here.

Abstract

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.

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