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Patterns of HER2 gene amplification and response to anti-HER2 therapies

Vicario, Rocio and Peg, Vicente and Morancho, Beatriz and fluck, mariano and zhang, Junjie and martinez-barriocanal, agueda and navarro jimenez, alexandra and Aura, Claudia and Burgues, Octavio and Lluch, Ana and Cortes, Javier and Nuciforo, Paulo and Rubio, Isabel and Maragoni, Elisabetta and Deeds, Jim and Boehm, Markus and Schlegel, Robert and Tabernero, Josep and Mosher, Rebecca and Arribas, Joaquin (2015) Patterns of HER2 gene amplification and response to anti-HER2 therapies. PLoS ONE, 10 (6). e0129876. ISSN 1932-6203

Abstract

A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK), is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs), which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ∼30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies.

Item Type: Article
Date Deposited: 21 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/25274

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