Overcoming Resistance to Trastuzumab in HER2-Amplified Breast Cancers

摘要

The receptor tyrosin kinase HER2 is amplified and/or overexpressed in 25-30% of all breast cancers. Blockade of HER2 with drugs such as trastuzumab or lapatinib has led to clinical benefit in patients with both metastatic and early-stage HER2-amplified breast cancer. However, resistance and disease progression always occurs in patients with metastatic disease, and many patients with early-stage breast cancer experience recurrences despite adjuvant treatment with one of these agents. To identify novel mechanisms of resistance to anti-HER2 therapy, I conducted a screen for molecules whose forced expression in HER2-amplified breast cancer cells confers resistance to HER2 inhibition. I screened an open reading frame library of approximately 600 kinases and kinase-related molecules. I found that both activated HRAS and the catalytic subunit of Protein Kinase A (PRKACA) conferred significant resistance to both compound-mediated and genetic inhibition of HER2. Upon further mechanistic investigation, I found that activated HRAS fully restored phospo- ERK levels in the presence of either of two HER2 tyrosine kinase inhibitors, but did not restore phospho-AKT1 levels. By contrast, PRKACA expression provided resistance to anti-HER2 treatment, but did not restore phospho-ERK or phospho-AKT1 levels. The mechanisms by which resistance is conferred by PRKACA are under continued investigation.