Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies

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.

包含编码人类表皮生长因子受体2（HER2，一种受体酪氨酸激酶，receptor tyrosine kinase, RTK）的基因的染色体区域，在20%的乳腺癌中发生扩增。尽管此类肿瘤通常可被靶向HER2的药物抑制，但它们常会产生耐药性并恢复恶性进展。双微体（double minutes, DMs）作为一类数量可被动态调控的染色体外实体，其携带的基因扩增被认为可促进针对RTKs的治疗耐药性的获得。本研究表明，约30%的HER2阳性肿瘤的HER2基因在双微体中发生扩增。然而，此类肿瘤对曲妥珠单抗（trastuzumab）的响应模式，与HER2基因在染色体内部发生扩增的肿瘤并无显著差异。此外，在多种抗HER2治疗耐药模型中，即便耐药性的产生伴随HER2蛋白表达的丢失，携带HER2的双微体的数量仍保持稳定。综上，临床与临床前数据均表明，尽管与既往预期相悖，但因携带HER2的双微体丢失而导致的HER2蛋白表达缺失，并非抗HER2治疗耐药的潜在机制。