Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors

Jialin Zhang; Gengshen Yin; Chunmiao Ye; Man Feng; Changhua Ji; Wenzhong Zhou; Fei Wang; Lixiang Yu; Shuya Huang; Zhigang Yu

doi:10.21147/j.issn.1000-9604.2024.02.03

Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors

Chin J Cancer Res. 2024 Apr 30;36(2):124-137. doi: 10.21147/j.issn.1000-9604.2024.02.03.

Authors

Jialin Zhang¹, Gengshen Yin¹, Chunmiao Ye^{1

2

3}, Man Feng⁴, Changhua Ji⁵, Wenzhong Zhou^{1

2

3}, Fei Wang^{1

2

3}, Lixiang Yu^{1

2

3}, Shuya Huang^{1

2

3}, Zhigang Yu^{1

2

3}

Affiliations

¹ Department of Breast Surgery, the Second Hospital of Shandong University, Jinan 250033, China.
² Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan 250033, China.
³ Shandong Provincial Engineering Laboratory of Translational Research on Prevention and Treatment of Breast Disease, Jinan 250033, China.
⁴ Department of Pathology, the Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences), Jinan 250031, China.
⁵ Department of Pathology, the Second Hospital of Shandong University, Jinan 250033, China.

PMID: 38751436
PMCID: PMC11090794
DOI: 10.21147/j.issn.1000-9604.2024.02.03

Abstract

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.

Keywords: Breast cancer; HER2; pertuzumab; primary resistance; pyrotinib; trastuzumab.