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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use*
-
Breast Neoplasms / drug therapy*
-
Breast Neoplasms / genetics*
-
Cell Line, Tumor
-
Disease Models, Animal
-
Drug Resistance, Neoplasm
-
Female
-
Gene Amplification*
-
Gene Dosage
-
Humans
-
Lapatinib
-
Molecular Targeted Therapy*
-
Quinazolines / pharmacology
-
Quinazolines / therapeutic use
-
Receptor, ErbB-2 / antagonists & inhibitors*
-
Receptor, ErbB-2 / genetics*
-
Trastuzumab / pharmacology
-
Trastuzumab / therapeutic use
-
Treatment Outcome
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
Quinazolines
-
Lapatinib
-
Receptor, ErbB-2
-
Trastuzumab
Grants and funding
This work has been supported by Novartis Pharma within the Consorcio de Investigación Biomédica y Oncológica Translacional Framework Programme, the Breast Cancer Research Foundation (BCRF), Spanish Association Against Cancer (Asociación Española Contra el Cáncer, AECC) and Instituto de Salud Carlos III (Intrasalud PI12/02536) to JA and the Network of Cooperative Cancer Research (RTICC-RD12/0036/0057/0070/0012) to JA, JT, JC and AL. AM-B is supported by a Juan de la Cierva postdoctoral fellow from Ministerio de Economía y Competitividad (JCI-2011-10960). JD, MB, RS, and RM are employed by Novartis and received funding in the form of salaries. The funders participated in study design, decision to publish, and preparation of the manuscript.