Kjær Ida, Lindsted Trine, Fröhlich Camilla, Olsen Jesper Velgaard, Horak Ivan David, Kragh Michael, Pedersen Mikkel Wandahl
Symphogen A/S, Ballerup, Denmark. The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Symphogen A/S, Ballerup, Denmark.
Mol Cancer Ther. 2016 Jul;15(7):1614-26. doi: 10.1158/1535-7163.MCT-15-0565. Epub 2016 May 11.
Squamous cell carcinomas (SCC) arising in upper parts of the aerodigestive tract are among the leading causes of death worldwide. EGFR has been found to play an essential role in driving the malignancy of SCC of the upper aerodigestive tract (SCCUAT), but, despite this, clinical results using a range of different EGFR-targeted agents have been disappointing. Cetuximab is currently the only EGFR-targeted agent approved by the FDA for treatment of SCCUAT. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to better understand the underlying mechanisms of cetuximab resistance in SCCUAT, we established from cetuximab-sensitive models cell lines with acquired resistance to cetuximab by continuous selective pressure in vitro and in vivo Our results show that resistant clones maintain partial dependency on EGFR and that receptor tyrosine kinase plasticity mediated by HER3 and IGF1R plays an essential role. A multitarget mAb mixture against EGFR, HER3, and IGF1R was able to overcome cetuximab resistance in vitro To our surprise, these findings could be extended to include SCCUAT cell lines with intrinsic resistance to cetuximab, suggesting that the triad consisting of EGFR, HER3, and IGF1R plays a key role in SCCUAT. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in SCCUAT. Mol Cancer Ther; 15(7); 1614-26. ©2016 AACR.
发生于上呼吸消化道的鳞状细胞癌（SCC）是全球主要的死亡原因之一。已发现表皮生长因子受体（EGFR）在驱动上呼吸消化道鳞状细胞癌（SCCUAT）的恶性肿瘤发展中起重要作用，尽管如此，使用一系列不同的EGFR靶向药物的临床结果却令人失望。西妥昔单抗是目前美国食品药品监督管理局（FDA）批准用于治疗SCCUAT的唯一EGFR靶向药物。然而，西妥昔单抗的内在和获得性耐药是有效治疗的一个主要问题。因此，更好地了解西妥昔单抗耐药的机制对于开发下一代抗体治疗药物具有重要价值。为了更好地了解SCCUAT中对西妥昔单抗耐药的潜在机制，我们通过在体外和体内持续施加选择压力，从对西妥昔单抗敏感的模型细胞系中建立了对西妥昔单抗具有获得性耐药的细胞系。我们的结果表明，耐药克隆对EGFR仍保持部分依赖性，并且由HER3和IGF1R介导的受体酪氨酸激酶可塑性起着至关重要的作用。一种针对EGFR、HER3和IGF1R的多靶点单克隆抗体混合物能够在体外克服西妥昔单抗耐药性。令我们惊讶的是，这些发现可以扩展到包括对西妥昔单抗具有内在耐药性的SCCUAT细胞系，这表明由EGFR、HER3和IGF1R组成的三联体在SCCUAT中起关键作用。因此，我们的结果为在SCCUAT中同时靶向EGFR、HER3和IGF1R提供了理论依据。《分子癌症治疗》；15(7)；1614 - 26。©2016美国癌症研究协会。
