Editors' ChoiceCancer

It takes three to tango

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Science Translational Medicine  09 Sep 2015:
Vol. 7, Issue 304, pp. 304ec153
DOI: 10.1126/scitranslmed.aad3067

Amplification of the human epidermal growth factor receptor 2 (HER2) oncogene has been recently described in a subset of esophagogastric and colorectal adenocarcinomas. However, targeted inhibition of these HER receptors via either monoclonal antibodies (mAb) or small-molecule tyrosine kinase inhibitors (TKIs) has been less successful than the results reported with HER2-directed therapies in breast tumors.

In this study, Leto et. al showed that dual blockade with trastuzumab and lapatinib is more effective than single-agent therapy in inducing regression of HER2-amplified patient-derived gastrointestinal (GI) tumorgrafts and cell-line xenografts; they also analyzed the molecular mechanisms underlying the co-operative signaling through parallel HER family pathways. The phosphorylation/activation of HER2, HER3, EGFR, and downstream transducers (ERK1/2, AKT, p70S6K, and GSK-3β) was evaluated by multiplex phosphoproteomics and conventional Western blotting. Trastuzumab monotherapy resulted in immediate reduction of HER3 phosphorylation and a delayed decrease in HER2 and EGFR activation, with minor consequences for downstream transducers, whereas lapatinib acutely reduced phosphorylation of all HER receptors but caused a delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and counteracted the eventual resumption of ERK and AKT phosphorylation, inducing durable signal abrogation. Similar results were obtained by using the irreversible pan-HER inhibitor afatinib, which also caused regression of HER2-amplified GI carcinomas in vivo.

In response to the clinical limitations of single HER inhibitor therapy, dual pathway blockade and the use of pan-HER inhibitors are gaining increased attention. The interactions between signaling pathways stimulated by various HER receptor combinations result in additional “autocrine” loops and likely provide an escape route by which specific blockade of a given receptor is overcome by compensatory signaling through parallel HER pathways. The study by Leto and colleagues provides a mechanistic appraisal of how such therapies impact HER2 signaling in GI cancers and offers insights on designing treatment approaches to overcome the shortcomings of single agent blockade.

S. M. Leto et al., Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas. Clin. Cancer Res. 10.1158/1078-0432.CCR-14-3066 (2015). [Abstract]

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