College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, USA.
Department of Mathematics, The University of Texas at Arlington, Arlington, TX 76019, USA.
Int J Mol Sci. 2022 Feb 3;23(3):1763. doi: 10.3390/ijms23031763.
Targeting dysregulated Ca signaling in cancer cells is an emerging chemotherapy approach. We previously reported that store-operated Ca entry (SOCE) blockers, such as RP4010, are promising antitumor drugs for esophageal cancer. As a tyrosine kinase inhibitor (TKI), afatinib received FDA approval to be used in targeted therapy for patients with EGFR mutation-positive cancers. While preclinical studies and clinical trials have shown that afatinib has benefits for esophageal cancer patients, it is not known whether a combination of afatinib and RP4010 could achieve better anticancer effects. Since TKI can alter intracellular Ca dynamics through EGFR/phospholipase C-γ pathway, in this study, we evaluated the inhibitory effect of afatinib and RP4010 on intracellular Ca oscillations in KYSE-150, a human esophageal squamous cell carcinoma cell line, using both experimental and mathematical simulations. Our mathematical simulation of Ca oscillations could fit well with experimental data responding to afatinib or RP4010, both separately or in combination. Guided by simulation, we were able to identify a proper ratio of afatinib and RP4010 for combined treatment, and such a combination presented synergistic anticancer-effect evidence by experimental measurement of intracellular Ca and cell proliferation. This intracellular Ca dynamic-based mathematical simulation approach could be useful for a rapid and cost-effective evaluation of combined targeting therapy drugs.
靶向癌细胞中失调的钙信号转导是一种新兴的化疗方法。我们之前报道过，储存操纵的钙内流（SOCE）阻断剂，如 RP4010，是一种很有前途的食管癌抗肿瘤药物。作为一种酪氨酸激酶抑制剂（TKI），阿法替尼已获得 FDA 批准，用于治疗 EGFR 突变阳性癌症患者的靶向治疗。虽然临床前研究和临床试验表明，阿法替尼对食管癌患者有一定益处，但尚不清楚阿法替尼和 RP4010 的联合应用是否能获得更好的抗癌效果。由于 TKI 可以通过 EGFR/磷脂酶 C-γ 途径改变细胞内钙动力学，因此在这项研究中，我们使用实验和数学模拟评估了阿法替尼和 RP4010 对人食管鳞癌细胞系 KYSE-150 细胞内钙振荡的抑制作用。我们对钙振荡的数学模拟可以很好地拟合实验数据，无论是单独使用阿法替尼或 RP4010，还是联合使用。在模拟的指导下，我们能够确定联合治疗中阿法替尼和 RP4010 的适当比例，并且通过细胞内钙和细胞增殖的实验测量，这种联合治疗具有协同抗癌作用的证据。这种基于细胞内钙动力学的数学模拟方法可能有助于快速、经济有效地评估联合靶向治疗药物。
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