Abstract
Simultaneous targeting of epidermal growth factor receptor (EGFR) and Met in cancer therapy is under pre-clinical and clinical evaluation. Here, we report the finding that treatment with EGFR inhibitors of various tumor cells, when stimulated with hepatocyte growth factor (HGF) and EGF, results in transient upregulation of phosphorylated AKT. Furthermore, EGFR inhibition in this setting stimulates a pro-invasive phenotype as assessed in Matrigel-based assays. Simultaneous treatment with AKT and EGFR inhibitors abrogates this invasive growth, hence functionally linking signaling and phenotype. This observation implies that during treatment of tumors a balanced ratio of EGFR and Met inhibition is required. To address this, we designed a bispecific antibody targeting EGFR and Met, which has the advantage of a fixed 2:1 stoichiometry. This bispecific antibody inhibits proliferation in tumor cell cultures and co-cultures with fibroblasts in an additive manner compared with treatment with both single agents. In addition, cell migration assays reveal a higher potency of the bispecific antibody in comparison with the antibodies' combination at low doses. We demonstrate that the bispecific antibody inhibits invasive growth, which is specifically observed with cetuximab. Finally, the bispecific antibody potently inhibits tumor growth in a non-small cell lung cancer xenograft model bearing a strong autocrine HGF-loop. Together, our findings strongly support a combination treatment of EGFR and Met inhibitors and further evaluation of resistance mechanisms to EGFR inhibition in the context of active Met signaling.
Highlights
Escape mechanisms occurring in cancer cells and which develop in response to inhibition of a specific signaling pathway often limit efficacy of targeted single-agent therapies.[1]
Spatially restricted increase of AKT phosphorylation was clearly observed in the membrane proximal region of A549-stimulated cells as described for H596 cells and in the context of epidermal growth factor receptor (EGFR) inhibition (Figure 1d), which might be indicative for a potential role in migration and invasion events
Experiments were performed with A431 cells, as this cell line is a good model to study motility in Matrigel chambers, it responds to cetuximab treatment with an increase in phosphoAKT when stimulated with hepatocyte growth factor (HGF) and displays increased invasion on treatment with HGF and/or EGF
Summary
Escape mechanisms occurring in cancer cells and which develop in response to inhibition of a specific signaling pathway often limit efficacy of targeted single-agent therapies.[1] Understanding the biology of such acquired and intrinsic resistance mechanisms in tumors is pivotal for devising future rational combination therapies. The inhibition of a single receptor tyrosine kinase signaling presents a good example of molecular networks, which mediate tumor escape.[2] A cross-talk of epidermal growth factor receptor (EGFR) and Met in transformed cells was already described in 2000 by Strom et al.[3] EGFR is a member of the. ErbB family of receptor tyrosine kinases consisting of EGFR (ErbB1), HER2/neu (ErbB2), HER3 (ErbB3) and HER4 (ErbB4).[4] Constitutive
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