Overcoming acquired resistance to cetuximab by dual targeting HER family receptors with antibody-based therapy

Molecular Cancer

Research

Neha Luthar¹  Hannah E Pearson¹  Mari Iida¹  Megan M Starr¹  Deric L Wheeler¹  John P Coan¹  Toni M Brand¹  Evan J Huppert¹  Harsh Bahrar¹  Ravi Salgia² 

[1] Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, 1111 Highland Ave, 53705, Madison, WI, USA;Division of Hematology/Oncology, Department of Medicine, University of Chicago, 60637, Chicago, IL, USA;

关键词: EGFR;    HER3;    U3-1287;    Cetuximab;    Acquired cetuximab-resistance;    Non-small cell lung cancer;    MAPK;    AKT;   

DOI  :  10.1186/1476-4598-13-242

 received in 2014-05-07, accepted in 2014-10-14,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundCetuximab, an anti-EGFR monoclonal antibody, is used to treat several cancers. However, many patients who initially respond to cetuximab acquire resistance. To examine mechanisms of acquired resistance, we developed a series of cetuximab-resistant (CtxR) clones derived from the cetuximab sensitive (CtxS) non-small cell lung cancer (NSCLC) cell line H226. Previous studies characterizing this model revealed that: 1) EGFR was robustly overexpressed in CtxR clones due to decreased EGFR ubiquitination and degradation and 2) CtxR clones expressed increased HER2 and HER3 activation resulting in constitutive activation of the PI3K/AKT signaling axis. These findings suggest that dual targeting HER family receptors would be highly beneficial in the CtxR setting.ResultsSince HER3 has been implicated in resistance to EGFR inhibitors, the efficacy of dually targeting both EGFR and HER3 in CtxR models was evaluated. First, EGFR and HER3 expression were knocked down with siRNAs. Compared to the CtxS parental cell line (HP), all CtxR clones exhibited robust decreases in cell proliferation upon dual knockdown. Analysis of CtxR clones indicated that neuregulin-1 was highly overexpressed compared to HP cells. Incubation of HP cells with neuregulin-1 rendered them resistant to cetuximab. Next, dual treatment of CtxR clones with cetuximab and the HER3 neutralizing monoclonal antibody (mAb) U3-1287 led to potent anti-proliferative effects. Blockade of EGFR with cetuximab resulted in inactivation of MAPK, while blockade of HER3 with U3-1287 resulted in the inactivation of AKT. Treatment with both mAbs resulted in knockdown of both signaling pathways simultaneously. HER2 was also strongly inactivated upon dual mAb therapy, suggesting that this treatment regimen can diminish signaling from three HER family receptors. De novo CtxR H226 mouse xenografts were established to determine if dual therapy could overcome acquired resistance to cetuximab in vivo. Tumors that had acquired resistance to cetuximab were significantly growth delayed upon dual treatment of U3-1287 and cetuximab compared to those continued on cetuximab only. Combinatorial-treated xenograft tumors expressed decreased Ki67 and increased cleaved caspase-3 levels compared to tumors treated with either monotherapy.ConclusionsThese studies demonstrate that dually targeting HER family receptors with antibody-based therapies can overcome acquired resistance to cetuximab.

【 授权许可】

Unknown   
© Iida et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.