TY - JOUR

T1 - Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity

T2 - Potential for mAb Mixtures

AU - Kjær, Ida

AU - Lindsted, Trine

AU - Fröhlich, Camilla

AU - Olsen, Jesper Velgaard

AU - Horak, Ivan David

AU - Kragh, Michael

AU - Pedersen, Mikkel Wandahl

N1 - Copyright {copyright, serif}2016, American Association for Cancer Research.

PY - 2016/7

Y1 - 2016/7

N2 - Squamous cell carcinomas (SCC) arising in upper parts of the aero-digestive tract (UAT) are among the leading causes of death worldwide. The epidermal growth factor receptor (EGFR) has been found to play an essential role in driving the malignancy of 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 RTK plasticity mediated by HER3 and IGF1R plays an essential role. A multi-target 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.

AB - Squamous cell carcinomas (SCC) arising in upper parts of the aero-digestive tract (UAT) are among the leading causes of death worldwide. The epidermal growth factor receptor (EGFR) has been found to play an essential role in driving the malignancy of 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 RTK plasticity mediated by HER3 and IGF1R plays an essential role. A multi-target 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.

U2 - 10.1158/1535-7163.MCT-15-0565

DO - 10.1158/1535-7163.MCT-15-0565

M3 - Journal article

C2 - 27196767

VL - 15

SP - 1614

EP - 1626

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 7

ER -