Triple-negative breast cancer (TNBC) is a devastating BC subtype. Its aggressiveness, allied to the lack of well-defined molecular targets, usually culminates in the appearance of metastases that account for poor prognosis, particularly when they develop in the brain. Nevertheless, TNBC has been associated with epidermal growth factor receptor (EGFR) overexpression, leading to downstream phosphoinositide 3-kinase (PI3K) signaling activation. We aimed to unravel novel drug candidates for TNBC treatment based on EGFR and/or PI3K inhibition. Using a highly metastatic TNBC cell line with brain tropism (MDA-MB-231 Br4) and a library of 27 drug candidates in silico predicted to inhibit EGFR, PI3K, or EGFR plus PI3K, and to cross the blood–brain barrier, we evaluated the effects on cell viability. The half maximal inhibitory concentration (IC50) of the most cytotoxic ones was established, and cell cycle and death, as well as migration and EGFR pathway intervenient, were further evaluated. Two dual inhibitors emerged as the most promising drugs, with the ability to modulate cell cycle, death, migration and proliferation, morphology, and PI3K/AKT cascade players such as myocyte enhancer factor 2C (MEF2C) and forkhead box P1 (FOXP1). This work revealed EGFR/PI3K dual inhibitors as strong candidates to tackle brain metastatic TNBC cells.
三阴性乳腺癌是一种极具破坏性的乳腺癌亚型。其侵袭性强且缺乏明确的分子靶点，通常导致转移灶的出现，造成不良预后，尤其是在发生脑转移时。然而，三阴性乳腺癌与表皮生长因子受体的过度表达相关，进而激活下游磷酸肌醇3-激酶信号通路。本研究旨在基于抑制EGFR和/或PI3K，探索治疗三阴性乳腺癌的新型候选药物。通过使用具有脑趋向性的高转移性三阴性乳腺癌细胞系，以及经计算机预测能抑制EGFR、PI3K或同时抑制两者且可穿透血脑屏障的27种候选药物库，我们评估了这些药物对细胞存活率的影响。确定了最具细胞毒性的药物的半数抑制浓度，并进一步评估了其对细胞周期、死亡、迁移及EGFR通路相关因子的影响。两种双重抑制剂显示出作为最有望的药物的潜力，能够调控细胞周期、死亡、迁移和增殖，改变细胞形态，并影响PI3K/AKT级联反应中的关键因子如肌细胞增强因子2C和叉头框蛋白P1。本研究表明EGFR/PI3K双重抑制剂是对抗脑转移性三阴性乳腺癌细胞的强效候选药物。
肿瘤(癌症)患者之家