Vicario Rocio, Peg Vicente, Morancho Beatriz, Zacarias-Fluck Mariano, Zhang Junjie, Martínez-Barriocanal Águeda, Navarro Jiménez Alexandra, Aura Claudia, Burgues Octavio, Lluch Ana, Cortés Javier, Nuciforo Paolo, Rubio Isabel T, Marangoni Elisabetta, Deeds James, Boehm Markus, Schlegel Robert, Tabernero Josep, Mosher Rebecca, Arribas Joaquín
Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Campus de la UAB, 08193, Bellaterra, Spain.
Pathology Department, Vall d'Hebron University Hospital, 08035, Barcelona, Spain.
PLoS One. 2015 Jun 15;10(6):e0129876. doi: 10.1371/journal.pone.0129876. eCollection 2015.
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.
一个包含编码HER2（一种受体酪氨酸激酶，RTK）基因的染色体区域在20%的乳腺癌中发生扩增。尽管这些肿瘤往往对针对HER2的药物有反应，但它们经常会产生耐药性并恢复恶性进展。双微体（DMs）中的基因扩增被认为有助于获得对靶向RTK疗法的耐药性，双微体是一种染色体外实体，其数量可动态调节。在这里，我们表明约30%的HER2阳性肿瘤在双微体中出现扩增。然而，这些肿瘤对曲妥珠单抗的反应方式与那些染色体上HER2基因扩增的肿瘤相似。此外，在不同的抗HER2治疗耐药模型中，即使耐药的获得与HER2蛋白表达的丧失同时发生，含有HER2的双微体数量仍保持不变。因此，临床和临床前数据均表明，尽管存在预期，但由于含有HER2的双微体丢失导致HER2蛋白表达丧失并非抗HER2治疗耐药的可能机制。
