Abstract
Although two growth factor receptors, EGFR and HER2, are amongst the best targets for cancer treatment, no agents targeting HER3, their kinase-defective family member, have so far been approved. Because emergence of resistance of lung tumors to EGFR kinase inhibitors (EGFRi) associates with compensatory up-regulation of HER3 and several secreted forms, we anticipated that blocking HER3 would prevent resistance. As demonstrated herein, a neutralizing anti-HER3 antibody we generated can clear HER3 from the cell surface, as well as reduce HER3 cleavage by ADAM10, a surface metalloproteinase. When combined with a kinase inhibitor and an anti-EGFR antibody, the antibody completely blocked patient-derived xenograft models that acquired resistance to EGFRi. We found that the underlying mechanism involves posttranslational downregulation of HER3, suppression of MET and AXL upregulation, as well as concomitant inhibition of AKT signaling and upregulation of BIM, which mediates apoptosis. Thus, although HER3 is nearly devoid of kinase activity, it can still serve as an effective drug target in the context of acquired resistance. Because this study simulated in animals the situation of patients who develop resistance to EGFRi and remain with no obvious treatment options, the observations presented herein may warrant clinical testing.
Highlights
Members of the human epidermal growth factor receptor (EGFR/HER) family, which includes, in addition to EGFR, HER2, HER3, and HER4, have been found overexpressed or mutated in several types of cancer [1]
The efficacy of combining a tyrosine kinase inhibitors (TKIs) and two monoclonal antibodies (mAbs), to EGFR and HER2, has so far been determined with cell lines cultivated in monolayer and xenografts derived from them [29]
An additional group was treated with a mixture of the antibodies and osimertinib
Summary
Members of the human epidermal growth factor receptor (EGFR/HER) family, which includes, in addition to EGFR, HER2, HER3, and HER4, have been found overexpressed or mutated in several types of cancer [1]. 10–30% of all patients with NSCLC (non-small cell lung cancer) carry activating mutations in the gene encoding EGFR [2,3,4,5,6]. The most common mechanism of resistance entails emergence of a secondary mutation (T790M) [11]. Other major mechanisms include amplification of genes encoding other receptor tyrosine kinases (RTKs), especially MET [12] and HER2 [13], overexpression of the hepatocyte growth factor, the respective receptor, MET [14,15], or yet another RTK, AXL [16]
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