Otifi Hassan M
Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia.
Onco Targets Ther. 2025 May 7;18:617-629. doi: 10.2147/OTT.S512184. eCollection 2025.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors, making it difficult to treat with targeted therapies. The Epidermal Growth Factor Receptor (EGFR) is overexpressed in TNBC and is crucial in promoting tumor growth and survival. Despite chemotherapeutics like 5-fluorouracil (5-FU), resistance remains a clinical challenge, underscoring the need for novel therapeutic strategies.
High-throughput virtual screening (HTVS) was employed to identify inhibitors targeting the inactive conformation of EGFR. The top-ranked compounds underwent molecular dynamics (MD) simulations and binding free energy calculations using Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA). MDA-MB-231, Hs578T, and 5-FU resistant- MDA-MB-231/5-FU cells were utilized to assess the anti-proliferative, EGFR, and apoptosis.
HTVS identified EG31 showing strong binding affinities towards EGFR. MD simulations confirmed the stable binding of EG31 to EGFR, as indicated by consistent Root Mean Square Deviation and hydrogen bond patterns throughout the simulation. MMPBSA calculations revealed highly favorable binding free energies. EG31 inhibited MDA-MB-231 and Hs578T proliferations with GI values of 498.90 nM and 740.73 nM, respectively. The compound decreased EGFR-positive populations and favored early and late-phase apoptosis in these cells. Furthermore, EG31 retained the anti-proliferative efficacy in the MDA-MB-231/5-FU cells, while 5-FU lost its effectiveness by 6-fold.
This study identified EG31 targeting the inactive conformation of EGFR, offering a promising therapeutic approach to overcome 5-FU resistance in TNBC. Further research could enhance treatment efficacy and provide a new avenue for managing this challenging cancer subtype.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，其特征是缺乏雌激素、孕激素和HER2受体，这使得用靶向疗法治疗变得困难。表皮生长因子受体（EGFR）在TNBC中过度表达，对促进肿瘤生长和存活至关重要。尽管有5-氟尿嘧啶（5-FU）等化疗药物，但耐药性仍然是一个临床挑战，这突出了对新型治疗策略的需求。
采用高通量虚拟筛选（HTVS）来鉴定靶向EGFR非活性构象的抑制剂。排名靠前的化合物使用分子力学泊松-玻尔兹曼表面积（MMPBSA）进行分子动力学（MD）模拟和结合自由能计算。利用MDA-MB-231、Hs578T和5-FU耐药的MDA-MB-231/5-FU细胞来评估抗增殖、EGFR和凋亡情况。
HTVS鉴定出EG31对EGFR具有很强的结合亲和力。MD模拟证实了EG31与EGFR的稳定结合，整个模拟过程中均方根偏差和氢键模式一致表明了这一点。MMPBSA计算显示出非常有利的结合自由能。EG31抑制MDA-MB-231和Hs578T增殖，GI值分别为498.90 nM和740.73 nM。该化合物减少了EGFR阳性群体，并促进了这些细胞的早期和晚期凋亡。此外，EG31在MDA-MB-231/5-FU细胞中保留了抗增殖功效，而5-FU的有效性降低了6倍。
本研究鉴定出靶向EGFR非活性构象的EG31，为克服TNBC中的5-FU耐药性提供了一种有前景的治疗方法。进一步的研究可以提高治疗效果，并为管理这种具有挑战性的癌症亚型提供新途径。
