SHR‐A1403 a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

摘要

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors ( ) have been used as the first‐line treatment of non‐small cell lung cancers ( ) harboring ‐activating mutations, but acquired resistance is ubiquitous and needs to be solved urgently. Here, we introduce an effective approach for overcoming resistance to the ‐ , 9291, in cells using ‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met)‐targeting antibody‐drug conjugate ( ) consisting of an anti‐c‐Met monoclonal antibody (c‐Met b) conjugated to a microtubule inhibitor. Resistant cells were established by exposing 827 to increasing concentrations of ‐ . c‐Met was found to be overexpressed in most resistant cells. 9291 resistance was partially restored by combination of 9291 and crizotinib only in resistant cells overexpressing phospho‐c‐Met, which synergistically inhibited c‐Met‐mediated phosphorylation of the downstream targets 1/2 and . In resistant cells overexpressing c‐Met, neither crizotinib nor c‐Met b was able to overcome 9291 resistance. In contrast, ‐A1403 strongly inhibited proliferation of 9291‐resistant 827 overexpressing c‐Met, regardless of the levels of c‐Met phosphorylation. ‐A1403 bound to resistant cells overexpressing c‐Met was internalized into cells and released associated microtubule inhibitor, resulting in cell‐killing activity that was dependent on c‐Met expression levels only, irrespective of the involvement of c‐Met or signaling in 9291 resistance. Consistent with its activity in vitro, ‐A1403 significantly inhibited the growth of 9291‐resistant 827 tumors and caused tumor regression in vivo. Thus, our findings show that ‐A1403 efficiently overcomes 9291 resistance in cells overexpressing c‐Met, and further indicate that c‐Met expression level is a biomarker predictive of ‐A1403 efficacy.