Format

Send to

Choose Destination
Mol Cancer Res. 2010 Jun;8(6):809-20. doi: 10.1158/1541-7786.MCR-09-0460. Epub 2010 Jun 8.

Cancer-associated fibroblasts derived from EGFR-TKI-resistant tumors reverse EGFR pathway inhibition by EGFR-TKIs.

Author information

1
Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Davis 6012, Los Angeles, CA 90048, USA.

Abstract

Epidermal growth factor receptor (EGFR) plays a critical role in oncogenesis, which makes it an attractive target for pharmacologic inhibition. Yet, EGFR inhibition with tyrosine kinase inhibitors (TKI) does not result in a measurable and sustainable clinical benefit in a vast majority of tumors. This emphasizes the need for further investigations into resistance mechanisms against EGFR-TKIs. We previously reported the generation of an in vivo adenocarcinoma model of EGFR-TKI-acquired resistance that was devoid of the known mechanisms of resistance. Using this same xenograft model, we now show that the tumor stroma plays an important role in limiting responsiveness to EGFR-TKIs. EGFR-TKI-resistant tumors display increased surface expression of CD44(hi)/CD24(lo) and markers of epithelial to mesenchymal transition (EMT), SNAI1, and N-cadherin. An in vivo green fluorescent protein-tagging approach reveals that the tumor stroma of the EGFR-TKI-resistant tumors is distinct in that 24% of its cancer-associated fibroblast (CAF) population is composed of EMT-derived tumor cells that represent the in vivo escape from EGFR-TKIs. We further show that EMT subpopulation-harboring CAFs isolated from the EGFR-TKI-resistant tumors are tumorigenic and express the biomarker of gefitinib resistance, epithelial membrane protein-1. Finally, we provide evidence that paracrine factors secreted from the EGFR-TKI-resistant CAFs mitigate the EGFR-TKI-mediated blockade of pEGFR and pMAPK in cocultured tumor cells, regardless of their EGFR mutational status. This is the first demonstration that the tumor stroma is modified with acquisition of EGFR-TKI resistance and that it further contributes in promoting drug resistance.

PMID:
20530582
PMCID:
PMC2891820
DOI:
10.1158/1541-7786.MCR-09-0460
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center