Dual Kinase Inhibition of EGFR and HER2 Overcomes Resistance to Cetuximab in a Novel In Vivo Model of Acquired Cetuximab Resistance

Abstract

Purpose Acquired resistance to cetuximab, a chimeric EGFR-targeting monoclonal antibody, is a widespread problem in the treatment of solid tumors. The paucity of preclinical models has limited investigations to determine the mechanism of acquired therapeutic resistance thereby limiting the development of effective treatments. The purpose of this study was to generate cetuximab-resistant tumors in vivo to characterize mechanisms of acquired resistance. Experimental Design We generated cetuximab-resistant clones from a cetuximab-sensitive bladder cancer cell line in vivo by exposing cetuximab-sensitive xenografts to increasing concentrations of cetuximab followed by validation of the resistant phenotype in vivo and in vitro using invasion assays. A candidate-based approach was used to examine the role of HER2 on mediating cetuximab resistance both in vitro and in vivo. Results We generated a novel model of cetuximab resistance and, for the first time in the context of EGFR-inhibitor resistance, we identified increased phosphorylation of a c-terminal fragment of HER2 (611-CTF) in cetuximab-resistant cells. Afatinib (BIBW-2992), an irreversible kinase inhibitor targeting EGFR and HER2, successfully inhibited growth of the cetuximab-resistant cells in vitro. When afatinib was combined with cetuximab in vivo, we observed an additive growth inhibitory effect in cetuximab-resistant xenografts. Conclusions These data suggest that the use of dual EGFR-HER2 kinase inhibitors can enhance responses to cetuximab, perhaps in part due to downregulation of 611-CTF. This study in a novel in vivo model provides a mechanistic rationale for ongoing phase I clinical trials using this combination treatment modality.

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

“…45 ADC has become a powerful treatment strategy to overcome drug resistance like trastuzumab resistance. 35 The efficacy of PanP-DM1 on the cancer cells that are refractory to EGFR-directed antibodies will be explored in a future research publication.…”

Melanoma-associated antigen expression and the efficacy of tyrosine kinase inhibitors in head and neck cancer

“…Recently, Hou et al (28) demonstrated a significant correlation between MAGE-A9 and -A11 expression and Her2/neu expression in breast cancer. There is a broad consensus that evasion of EGFR-targeted therapy is facilitated by the activation of alternative receptors, including Her2/neu, as well as their downstream signaling pathways (29,30). Even if TKI treatment combined with cisplatin and radiotherapy failed to improve progression-free survival in unselected cohorts, erlotinib and gefitinib may function as chemopreventive drugs (31).…”

EGFR and NF-κB: partners in cancer

“…EGFR point mutations are not the only mechanism by which cancer cells are (or become) resistant to EGFR inhibitors. Activation of other RTKs such as ERBB2/ HER2 also occurs in cells resistant to cetuximab, an EGFR-targeting monoclonal antibody, which paves the way for the dual inhibition of both EGFR and HER2 to improve the clinical response [22]. Signaling from ERBB3/ HER3 is also specifically activated in epithelial malignancies treated with EGFR inhibitors [23][24][25].…”