Epidermal growth factor receptor signaling in precancerous keratinocytes promotes neighboring head and neck cancer squamous cell carcinoma cancer stem cell-like properties and phosphoinositide 3-kinase inhibitor insensitivity.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a "precancerous field," with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of >1300 analytes in the media conditioned by NOK cells and HNSCC cells ± PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance.

• Authors: Khoa A Nguyen, Madison J Keith, Stephen B Keysar, Spencer C Hall, Anamol Bimali, Antonio Jimeno, Xiao-Jing Wang, Christian D Young
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 61 Issue 7 Pg. 664-676 (07 2022) ISSN: 1098-2744 [Electronic] United States
• PMID: 35417043 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Wiley Periodicals LLC.

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Receptors, Fibroblast Growth Factor
• Phosphatidylinositol 3-Kinase
• EGFR protein, human
• ErbB Receptors

Topics

• Carcinoma, Squamous Cell (genetics)
• Cell Line, Tumor
• ErbB Receptors (metabolism)
• Head and Neck Neoplasms (drug therapy)
• Humans
• Keratinocytes (metabolism)
• Neoplastic Stem Cells (pathology)
• Phosphatidylinositol 3-Kinase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Precancerous Conditions
• Receptors, Fibroblast Growth Factor
• Squamous Cell Carcinoma of Head and Neck (drug therapy)
• Tumor Microenvironment