Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance

Cancers

Brent Larson¹  Heinz-Josef Lenz²  ShannonM. Mumenthaler³  Anthony Jusuf³  Oscar Chen³  Roy Lau³  MichaelE. Doche³  ColleenM. Garvey³  EmmaJ. Fong³  RenX. Sun³  Alyssa Sanchez³ 

[1] Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA;

关键词: colorectal cancer;    cancer-associated fibroblasts;    epidermal growth factor;    cetuximab;    drug-resistance;    tumor microenvironment;   

DOI  :  10.3390/cancers12061393

来源: DOAJ

【 摘 要 】

Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor receptor (EGFR), is given in combination with chemotherapy as the standard of care for a subset of metastatic colorectal cancer patients. The overall response to this treatment is underwhelming and, while genetic mutations that confer resistance have been identified, it is still not known why this drug is ineffective for some patients. We discovered that cancer-associated fibroblasts (CAFs), a major cellular subset of the tumor stroma, can provide a source of cancer cell resistance. Specifically, we observed that upon treatment with cetuximab, CAFs increased their secretion of EGF, which was sufficient to render neighboring cancer cells resistant to cetuximab treatment through sustained mitogen-activated protein kinases (MAPK) signaling. Furthermore, we show the cetuximab-induced EGF secretion to be specific to CAFs and not to cancer cells or normal fibroblasts. Altogether, this work emphasizes the importance of the tumor microenvironment and considering the potential unintended consequences of therapeutically targeting cancer-driving proteins on non-tumorigenic cell types.

【 授权许可】

Unknown