Developing a mathematical model of intracellular Calcium dynamics for evaluating combined anticancer effects of afatinib and RP4010 in esophageal cancer

Chang Y, Funk M, Roy S, Stephenson ER, Choi S, Kojouharov HV, Chen B, Pan Z. 2022. Developing a mathematical model of intracellular Calcium dynamics for evaluating combined anticancer effects of afatinib and RP4010 in esophageal cancer. International Journal of Molecular Sciences. 23(3), 1763.

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Author
Chang, Yan; Funk, Marah; Roy, Souvik; Stephenson, Elizabeth RISTA; Choi, Sangyong; Kojouharov, Hristo V.; Chen, Benito; Pan, Zui
Department
Abstract
Targeting dysregulated Ca2+ signaling in cancer cells is an emerging chemotherapy approach. We previously reported that store-operated Ca2+ 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 Ca2+ dynamics through EGFR/phospholipase C-γ pathway, in this study, we evaluated the inhibitory effect of afatinib and RP4010 on intracellular Ca2+ oscillations in KYSE-150, a human esophageal squamous cell carcinoma cell line, using both experimental and mathematical simulations. Our mathematical simulation of Ca2+ 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 Ca2+ and cell proliferation. This intracellular Ca2+ dynamic-based mathematical simulation approach could be useful for a rapid and cost-effective evaluation of combined targeting therapy drugs.
Publishing Year
Date Published
2022-02-01
Journal Title
International Journal of Molecular Sciences
Acknowledgement
This work was partially supported by grants from National Institutes of Health (NIH) (R01 CA185055, S10OD0252300) and The University of Texas System STARs Award (to Z.P.), The University of Texas at Arlington Interdisciplinary Research Program (to B.C., H.V.K. and Z.P.).
Volume
23
Issue
3
Article Number
1763
ISSN
eISSN
IST-REx-ID

Cite this

Chang Y, Funk M, Roy S, et al. Developing a mathematical model of intracellular Calcium dynamics for evaluating combined anticancer effects of afatinib and RP4010 in esophageal cancer. International Journal of Molecular Sciences. 2022;23(3). doi:10.3390/ijms23031763
Chang, Y., Funk, M., Roy, S., Stephenson, E. R., Choi, S., Kojouharov, H. V., … Pan, Z. (2022). Developing a mathematical model of intracellular Calcium dynamics for evaluating combined anticancer effects of afatinib and RP4010 in esophageal cancer. International Journal of Molecular Sciences. MDPI. https://doi.org/10.3390/ijms23031763
Chang, Yan, Marah Funk, Souvik Roy, Elizabeth R Stephenson, Sangyong Choi, Hristo V. Kojouharov, Benito Chen, and Zui Pan. “Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of Afatinib and RP4010 in Esophageal Cancer.” International Journal of Molecular Sciences. MDPI, 2022. https://doi.org/10.3390/ijms23031763.
Y. Chang et al., “Developing a mathematical model of intracellular Calcium dynamics for evaluating combined anticancer effects of afatinib and RP4010 in esophageal cancer,” International Journal of Molecular Sciences, vol. 23, no. 3. MDPI, 2022.
Chang Y, Funk M, Roy S, Stephenson ER, Choi S, Kojouharov HV, Chen B, Pan Z. 2022. Developing a mathematical model of intracellular Calcium dynamics for evaluating combined anticancer effects of afatinib and RP4010 in esophageal cancer. International Journal of Molecular Sciences. 23(3), 1763.
Chang, Yan, et al. “Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of Afatinib and RP4010 in Esophageal Cancer.” International Journal of Molecular Sciences, vol. 23, no. 3, 1763, MDPI, 2022, doi:10.3390/ijms23031763.
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