Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors
Jialin Zhang1, Gengshen Yin1, Chunmiao Ye1,2,3
1Department of Breast Surgery, the Second Hospital of Shandong University, Jinan 250033, China.
Objective:
Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2 (HER2)-positive (+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown.
Methods:
HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab.
Results:
Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model.
Conclusions:
Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.
Insights
Pyrotinib shows anti-cancer effects in HER2+ breast cancer, even with trastuzumab resistance. Pyrotinib plus trastuzumab is more effective than pertuzumab plus trastuzumab for HER2+ breast cancer with primary trastuzumab resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Primary resistance to trastuzumab is a significant challenge in treating human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
- Pyrotinib, a novel tyrosine kinase inhibitor, has demonstrated efficacy in HER2-positive breast cancer, but its role in cases with primary trastuzumab resistance is not well-defined.
Purpose of the Study:
- To investigate the efficacy of pyrotinib, alone and in combination with trastuzumab, in HER2-positive breast cancer models with primary resistance to trastuzumab.
- To compare the therapeutic effects of pyrotinib plus trastuzumab with pertuzumab plus trastuzumab in preclinical models.
Main Methods:
- HER2-positive breast cancer cells, both sensitive and primarily resistant to trastuzumab, were treated with trastuzumab, pyrotinib, or combinations.
- Assays included cell proliferation, migration, invasion, and analysis of HER2 downstream signaling pathways (PI3K/AKT and RAS/RAF/MAPK/ERK).
- In vivo efficacy was evaluated using a xenograft mouse model with primary trastuzumab resistance, comparing pyrotinib plus trastuzumab to pertuzumab plus trastuzumab.
Main Results:
- Pyrotinib inhibited proliferation, migration, and invasion in both trastuzumab-sensitive and -resistant HER2-positive cells by targeting key signaling pathways.
- Trastuzumab alone showed no effect in primary resistant cells, while pyrotinib demonstrated therapeutic effects.
- Pyrotinib plus trastuzumab showed superior efficacy over pyrotinib alone and was more effective than pertuzumab plus trastuzumab in inhibiting tumor growth and downstream HER2 signaling in resistant models.
Conclusions:
- Pyrotinib-containing regimens exhibit anti-cancer activity in HER2-positive breast cancer, including cases with primary trastuzumab resistance.
- The combination of pyrotinib and trastuzumab demonstrated greater efficacy than trastuzumab and pertuzumab in preclinical models of trastuzumab-resistant HER2-positive breast cancer.
- These findings support the clinical investigation of dual anti-HER2 therapies combining small molecule inhibitors with antibodies for resistant HER2-positive breast cancer.
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