Inhibition of TGF-β Enhances the In Vivo Antitumor Efficacy of EGF Receptor–Targeted Therapy

Abstract

EGF receptor (EGFR)–targeted monoclonal antibodies (mAb), such as cetuximab, execute their antitumor effect in vivo via blockade of receptor–ligand interactions and engagement of Fcγ receptors on immune effector cells that trigger antibody-dependent cell-mediated cytotoxicity (ADCC). We show that tumors counteract the in vivo antitumor activity of anti-EGFR mAbs by increasing tumor cell-autonomous expression of TGF-β. We show that TGF-β suppresses the expression of key molecular effectors of immune cell–mediated cytotoxicity, including Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-γ. In addition to exerting an extrinsic inhibition of the cytotoxic function of immune effectors, TGF-β–mediated activation of AKT provides an intrinsic EGFR-independent survival signal that protects tumor cells from immune cell–mediated apoptosis. Treatment of mice-bearing xenografts of human head and neck squamous cell carcinoma with cetuximab resulted in emergence of resistant tumor cells that expressed relatively higher levels of TGF-β compared with untreated tumor-bearing mice. Although treatment with cetuximab alone forced the natural selection of TGF-β–overexpressing tumor cells in nonregressing tumors, combinatorial treatment with cetuximab and a TGF-β–blocking antibody prevented the emergence of such resistant tumor cells and induced complete tumor regression. Therefore, elevated levels of TGF-β in the tumor microenvironment enable tumor cells to evade ADCC and resist the antitumor activity of cetuximab in vivo. Our results show that TGF-β is a key molecular determinant of the de novo and acquired resistance of cancers to EGFR-targeted mAbs, and provide a rationale for combinatorial targeting of TGF-β to improve anti-EGFR–specific antibody therapy of EGFR-expressing cancers.

Downregulation of the TGFβ Pseudoreceptor BAMBI in Non–Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion

“…In addition, the targeting of EGFR signaling by the EGFR antibody Cetuximab in a xenograft model of head and neck cancer resulted in emergence of resistant tumor cells that expressed relatively higher levels of TGFb and elevated levels of TGFb in the tumor microenvironment enable tumor cells to evade antibodydependent cell-mediated cytotoxicity and resist the antitumor activity of Cetuximab in vivo. These results show that TGFb is a key molecular determinant of resistance of cancers to EGFRtargeted therapy (52).…”

An Unconventional KITENIN/ErbB4-Mediated Downstream Signal of EGF Upregulates c-Jun and the Invasiveness of Colorectal Cancer Cells

“…As for the new molecular determinants of resistance to anti-EGFR agents, proto-oncogene securin promotes resistance to gefitinib-induced apoptosis via an EGFRindependent pathway in human cancer cells (26) and TGFb provides an intrinsic EGFR-independent survival signal that protects squamous cancer cells from cetuximab-dependent cellular cytotoxicity (27). In this study, we observed that KITENIN was significantly highly expressed in tumor tissues from metastatic colorectal cancer patients with wild-type KRAS who showed poor responses to cetuximab/conventional chemotherapy after the initial stages of treatment.…”

Combination cancer immunotherapy and new immunomodulatory targets

“…Galunisertib has a well-defined therapeutic window based on dampening, but not shutting down, receptor signalling 164 and has shown clinical activity in a variety of solid tumour models. This and other TGFβ inhibitors have been tested in combination therapy in preclinical models, showing synergy with other therapeutic modalities such as chemotherapy 165 and growth factor inhibition 166 . In a transgenic mouse melanoma model, galunisertib showed synergistic activity with anti-CTLA4 therapy 167 .…”