Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer
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Chiara Arienti1, Michele Zanoni1, Sara Pignatta1, Alberto Del Rio2,3, Silvia Carloni1, Michela Tebaldi1, Gianluca Tedaldi1, Anna Tesei1
1Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
2Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna, Italy
3Innovamol Srls, Modena, Italy
Chiara Arienti, e-mail: firstname.lastname@example.org
Anna Tesei, e-mail: email@example.com
Keywords: trastuzumab resistance, gastric cancer, HER family receptors, HER signaling pathways, IQGAP1
Received: October 19, 2015 Accepted: February 11, 2016 Published: February 22, 2016
HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2-signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones.
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