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

Abstract

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.

Cancer-associated fibroblasts: overview, progress, challenges, and directions

“…Similarly, studies have found that the TME and CAFs (its main component) are among the main reasons for the development of therapeutic resistance in tumors. Cetuximab can specifically induce CAFs in colorectal cancer to secrete a large amount of epidermal growth factor, which in turn mediates MAPK signal transduction to resist cetuximab therapy, implying that targeting CAFs in the TME has potential clinical therapeutic value [69]. miR-21 is an important regulator of the activation of CAFs, and its expression is noted in tumor cells and CAFs [70].…”

Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer

“…Recently, disturbances in the tumor microenvironment caused by EGFR antibody have also been recognized as factors in treatment failure. Garvey et al reported that cetuximab causes cancer-associated fibroblasts to secrete more EGF and reactivate mitogen-activated protein kinase signaling in para-CRC cells [32]. Critically, it is important to understand the interaction between tumor cells and the tumor microenvironment in anti-EGFR therapy resistance.…”

Fibroblasts in cancer dormancy: foe or friend?

“…Barrios et al found out that FGF-2 could induce dormancy of breast cancer cells by activating PI3K/Akt pathway in an integrin α5β1-dependent or independent way [ 53 ]. In colorectal cancer, the administration of cetuximab could induce EGF secretion of CAFs only, exclusive of cancer cells and normal fibroblasts [ 54 ]. And Clark et al established an ex vivo hepatic microphysiological system in which they used EGF and lipopolysaccharide to activate the residual dormant breast cancer cells after chemotherapy [ 55 ].…”