2. Academic Validation
  3. PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer

PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer

  • Cancer Lett. 2024 Jul 8:598:217112. doi: 10.1016/j.canlet.2024.217112.
Hongyan Zhang 1,  Longlong Zhang 2,  Yuna He 3,  Dewei Jiang 4,  Jian Sun 5,  Qianmei Luo 4,  Huichun Liang 4,  Tiantian Wang 6,  Fubing Li 2,  Yu Tang 5,  Zimo Yang 3,  Wenjing Liu 7,  Yu Rao 8,  Ceshi Chen 9
Affiliations

Affiliations

  • 1 Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China; Medical School, Kunming University of Science and Technology, Kunming, 650500, China.
  • 2 Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
  • 3 State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
  • 4 Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
  • 5 The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China.
  • 6 Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; School of Life Science, University of Science & Technology of China, Hefei, 230027, Anhui, China.
  • 7 The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China. Electronic address: lwj9149@163.com.
  • 8 State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. Electronic address: yrao@tsinghua.edu.cn.
  • 9 Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China; The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China. Electronic address: chenc@kmmu.edu.cn.
PMID: 38986734 DOI: 10.1016/j.canlet.2024.217112
Abstract

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast Cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast Cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast Cancer xenograft tumors and patient-derived breast Cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.

Keywords

AKT; Alpelisib; HER2 resistance; Lapatinib; PI3K; PIK3CA mutation; PROTAC.

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