Targeting erbB Pathways in Breast Cancer: Dual Kinase Inhibition for Brain Metastasis and Prevention of p185HER2/Neu Tumor Development.

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC ACS Applied Electronic Materials Pub Date : 2024-10-30 eCollection Date: 2024-01-01 DOI:10.2147/BCTT.S490904
Peeyush N Goel, Makoto Katsumata, Wei Qian, Sunil Mathur, Mei Q Ji, Arabinda Samanta, Payal Grover, George Sgouros, Jenny C Chang, Mark I Greene
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Abstract

Background: Breast cancer predominantly affects women and poses challenges in the treatment of both local and advanced diseases. In a previous study, we reported the effectiveness of ER121, a structurally resolved small compound specifically designed to target human cancers expressing or overexpressing mutant EGFR and HER2.

Purpose: The objective of this study is to assess the efficacy and toxicity of ER121 in metastatic and triple negative breast cancer (TNBC, HER2+) cells and tumor models. The Herceptin-resistant breast cancer cell line JIMT-1 was used in an in vivo tumor model, and MMTV-erbB2 (Fo5) transgenic mice models were used to evaluate the efficacy and safety of ER121 as neoadjuvant.

Methods: ER121 treatment focusing on experimental brain metastasis in TNBC, HER2+ model, was quantified by total flux employing the In Vivo Imaging System (IVIS). We also compared the brain tissue from the treated and the controls groups. Additionally, ER121 was evaluated in JIMT-1, a Herceptin-resistant breast cancer cell line, both in vitro and in vivo tumor model. We also administered ER121 orally in neoadjuvant model with the MMTV-erbB2 (Fo5) transgenic mice, the survival rates were compared with the control group. Tumor-free survival of multiple treated groups were analyzed by Kaplan-Meier analysis employing the log-rank test with the Bonferroni correction using R Statistical Software.

Results: In this study, we present findings indicating that ER121 treatment significantly attenuated breast tumor growth using a TNBC, HER2+ model, focusing on experimental brain metastasis, as quantified by total flux employing IVIS. These observations were further corroborated by analysis of brain tissue from the treatment group compared to controls. Data is presented as Mean ± S.D. statistical significance was calculated using Student t test (*p < 0.05). Additionally, ER121 significantly inhibited JIMT-1, a Herceptin-resistant breast cancer cell line was used in vivo xenograft model. Additionally, we used a neoadjuvant model with the MMTV-erbB2 (Fo5) transgenics and the tumor-free survival rates exhibited a remarkable difference between the control and treated groups when ER121 was administered orally. We found statistically significant p values of 0.048 employing log-rank test with Bonferroni Correction for comparing ER121 high, ER121 Low, Herceptin and PBS groups. All analyses were performed using R Statistical Software.

Conclusion: ER121 is a non-toxic small-molecule erbB kinase inhibitor and holds promise as an oral and systemic therapeutic agent for treating progressive erbB-driven tumors in therapeutic settings. Moreover, ER121 shows potential as a preventive therapy in neoadjuvant settings for erbB2-associated tumors and when administered systemically can dramatically limit erbB2 brain metastases in animal models.

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靶向乳腺癌中的 erbB 通路:双重激酶抑制脑转移和预防 p185HER2/Neu 肿瘤发展。
背景:乳腺癌主要影响女性,给局部和晚期疾病的治疗带来了挑战。目的:本研究旨在评估 ER121 在转移性和三阴性乳腺癌(TNBC,HER2+)细胞和肿瘤模型中的疗效和毒性。赫赛汀耐药乳腺癌细胞系JIMT-1被用于体内肿瘤模型,MMTV-erbB2(Fo5)转基因小鼠模型被用于评估ER121作为新辅助药物的疗效和安全性:ER121治疗的重点是TNBC、HER2+模型的实验性脑转移,采用体内成像系统(IVIS)对总通量进行量化。我们还比较了治疗组和对照组的脑组织。此外,ER121 还在赫赛汀耐药乳腺癌细胞系 JIMT-1 的体外和体内肿瘤模型中进行了评估。我们还在MMTV-erbB2(Fo5)转基因小鼠的新辅助治疗模型中口服了ER121,并与对照组的生存率进行了比较。多个治疗组的无瘤生存率通过 Kaplan-Meier 分析法进行分析,该分析法采用对数秩检验,并使用 R 统计软件进行 Bonferroni 校正:在这项研究中,我们发现ER121治疗能显著抑制TNBC、HER2+模型中乳腺肿瘤的生长,重点是实验性脑转移,并通过IVIS的总通量进行量化。对治疗组与对照组脑组织的分析进一步证实了这些观察结果。数据以均数±标准差表示,统计学意义采用学生 t 检验(*p 结论):ER121是一种无毒的小分子erbB激酶抑制剂,有望作为一种口服和全身治疗药物,用于治疗进展期erbB驱动的肿瘤。此外,ER121 还具有在新辅助治疗中预防 erbB2 相关肿瘤的潜力,在动物模型中全身给药可显著限制 erbB2 脑转移。
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CiteScore
7.20
自引率
4.30%
发文量
567
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