Tian Ziyin, Yang Yan, Wu He, Chen Yongye, Jia Hao, Zhu Lei, He Runjia, Jin Yibo, Zhou Bei, Ge Chunpo, Sun Yanxia, Yang Yun
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
Department of Nucleus Radiation-related Injury Treatment, PLA Rocket Force Characteristic Medical Center, Beijing, China.
Heliyon. 2022 Aug 29;8(8):e10410. doi: 10.1016/j.heliyon.2022.e10410. eCollection 2022 Aug.
The dual tyrosine kinase (EGFR/HER2) inhibitor lapatinib is currently used to clinically treat HER2-positive breast cancer. However, a majority of patients do not respond to lapatinib therapy within 6 months. Therefore, potentiating the anti-tumor effect of lapatinib by combination treatment has a great potential to overcome the obstacle. Herein, we aim to investigate the anti-tumor activity of lapatinib in combination with brusatol and explore the potential mechanism involved in the combinatorial treatment. Our findings revealed that the Nrf2 inhibitor brusatol potently enhanced the anti-tumor effect of lapatinib against SK-BR-3, SK-OV-3 and AU565 cancer cells in a synergistic manner. Furthermore, we found that lapatinib plus brusatol more effectively decreased Nrf2 level and induced ROS generation in both SK-BR-3 and SK-OV-3 cells. Moreover, we also observed a significant reduction on the phosphorylation of HER2, EGFR, AKT and ERK1/2 in SK-BR-3 and SK-OV-3 cells when treated with lapatinib plus brusatol compared to either agent alone. More importantly, brusatol significantly augmented the anti-tumor effects of lapatinib in the SK-OV-3 xenograft model. In summary, these data provide a potential rationale for the combination of brusatol and lapatinib on the treatment of HER2-positive cancers.
双酪氨酸激酶（EGFR/HER2）抑制剂拉帕替尼目前用于临床治疗HER2阳性乳腺癌。然而，大多数患者在6个月内对拉帕替尼治疗无反应。因此，通过联合治疗增强拉帕替尼的抗肿瘤作用具有克服这一障碍的巨大潜力。在此，我们旨在研究拉帕替尼与布鲁斯他汀联合的抗肿瘤活性，并探索联合治疗中涉及的潜在机制。我们的研究结果表明，Nrf2抑制剂布鲁斯他汀以协同方式有效增强了拉帕替尼对SK-BR-3、SK-OV-3和AU565癌细胞的抗肿瘤作用。此外，我们发现拉帕替尼加布鲁斯他汀更有效地降低了SK-BR-3和SK-OV-3细胞中的Nrf2水平并诱导了ROS生成。此外，与单独使用任何一种药物相比，当用拉帕替尼加布鲁斯他汀处理时，我们还观察到SK-BR-3和SK-OV-3细胞中HER2、EGFR、AKT和ERK1/2的磷酸化显著降低。更重要的是，布鲁斯他汀显著增强了拉帕替尼在SK-OV-3异种移植模型中的抗肿瘤作用。总之，这些数据为布鲁斯他汀和拉帕替尼联合治疗HER2阳性癌症提供了潜在的理论依据。
