Cetuximab Attenuates Its Cytotoxic and Radiosensitizing Potential by Inducing Fibronectin Biosynthesis

Abstract

Inherent and acquired resistance to targeted therapeutics continues to emerge as a major clinical obstacle. For example, resistance to EGF receptor targeting occurs commonly, more so than was expected, on the basis of preclinical work. Given emerging evidence that cancer cell-substrate interactions are important determinants of therapeutic sensitivity, we examined the impact of cell-fibronectin interactions on the efficacy of the EGF receptor antibody cetuximab, which is used widely for lung cancer treatment. Our results revealed the potential for cell-fibronectin interactions to induce radioresistance of human non-small cell lung cancer cells. Cell adhesion to fibronectin enhanced tumor cell radioresistance and attenuated the cytotoxic and radiosensitizing effects of cetuximab. Both in vitro and in vivo, we found that cetuximab treatment led to a remarkable induction of fibronectin biosynthesis. Mechanistic analyses revealed the induction was mediated by a p38-MAPK-ATF2 signaling pathway and that RNAi-mediated inhibition of fibronectin could elevate the cytotoxic and radiosensitizing potential of cetuximab. Taken together, our findings show how cell adhesion blunts cetuximab, which, by inducing fibronectin, generates a self-attenuating mechanism of drug resistance.

Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells

“…10 In brief, 5 × 10 5 cells were embedded in 0.5 mg/ml lrECM. At 24 h after seeding, cells were treated with AIIB2 or IgG#1 (10 μg/ml), irradiated (6 Gy Table 2).…”

“…[3][4][5][6] We and other groups have demonstrated enhanced tumor cell sensitivity to radiotherapy, chemotherapy and molecular drugs as a result of antibody-mediated β1 integrin targeting in various preclinical cancer models including head and neck, lung, brain, breast and leukemia. [7][8][9][10][11][12] Integrins are transmembrane cell adhesion receptors for ECM proteins. 18 α and 8 β integrin subunits can form 24 different α/β integrin heterodimers by non-covalent binding.…”

LIM-only protein FHL2 critically determines survival and radioresistance of pancreatic cancer cells

“…For immunofluorescence staining, cells were prepared, stained and images were acquired with the LSM meta 510 (Zeiss) as published [28]. Human tissues were obtained from pathology archival material in a blinded fashion as approved by the ethics committee of the Dresden University of Technology (Germany).…”

EGFR and β1-integrin targeting differentially affect colorectal carcinoma cell radiosensitivity and invasion

“…Numerous cytoplasmic protein kinases, including focal adhesion kinase (FAK), and adapter proteins facilitate downstream integrin signaling to control cell survival, therapy resistance and metastasis. In addition to hampering invasion, we and others have demonstrated that b1 integrin targeting enhances radiochemosensitivity in head and neck cancer, glioblastoma, lung cancer, pancreatic cancer, breast cancer and leukemia [10][11][12][13][14][15][16][17]. In head and neck cancers, simultaneous b1 integrin/EGFR targeting elicited stronger radiosensitization than monotherapies [18].…”