Conjugates Derived from Lapatinib Derivatives with Cancer Cell Stemness Inhibitors Effectively Reversed Drug Resistance in Triple-Negative Breast Cancer

Increasing
evidence indicates that the cancer stem cell (CSC) subpopulation
contributes to the therapeutic resistance and metastasis of tumors,
leading to patient recurrence and death. Herein, we designed and synthesized
several compounds by conjugating lapatinib derivatives with different
CSC inhibitors to treat with lapatinib-induced MDA-MB-231 drug-resistant
cells. In vitro biological studies indicated that 3a showed strong cytotoxicity and EGFR enzyme inhibitory activity
and effectively reversed lapatinib-mediated resistance of MDA-MB-231
cells via inhibiting triple-negative breast cancer (TNBC) cell stemness
and the AKT/ERK signaling pathway. In addition, 3a was
capable of strongly suppressing the invasion and migration of TNBC
cells by inhibiting the Wnt/β-catenin signaling pathway and
MMP-2 and MMP-9 protein expression. In vivo tumorigenicity
tests showed that 3a could inhibit the occurrence of
TNBC by inhibiting BCSCs, proving 3a is a potential EGFR
and CSC dual inhibitor for TNBC treatment.

日益增多的证据表明，癌干细胞（CSC）亚群对肿瘤的耐药性和转移起着重要作用，导致患者复发和死亡。本研究中，我们通过将拉帕替尼衍生物与不同的CSC抑制剂偶联，设计并合成了一系列化合物，以治疗由拉帕替尼诱导的MDA-MB-231耐药细胞。体外生物学研究表明，3a表现出显著的细胞毒性和EGFR酶抑制活性，并能够通过抑制三阴性乳腺癌（TNBC）细胞的干性以及AKT/ERK信号通路，有效逆转MDA-MB-231细胞的拉帕替尼介导的耐药性。此外，3a通过抑制Wnt/β-catenin信号通路和MMP-2及MMP-9蛋白表达，能够强烈抑制TNBC细胞的侵袭和迁移。体内肿瘤发生性测试显示，3a能够通过抑制BCSCs来抑制TNBC的发生，证实3a是治疗TNBC的潜在EGFR和CSC双重抑制剂。