Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of Afatinib and RP4010 in Esophageal Cancer

Chang, Yan; Funk, Marah; Roy, Souvik; Stephenson, Elizabeth; Choi, Sangyong; Kojouharov, Hristo V.; Chen, Benito; Pan, Zui

doi:10.3390/ijms23031763

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Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of Afatinib and RP4010 in Esophageal Cancer

^1,†,

^2,†,

^2,3,

^1,4,

^2,*,

and

^1,*

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

Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria

⁴

Department of Nutritional Sciences, University of Connecticut, Mansfield, CT 06269, USA

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Academic Editor: Dimitra Gkika

Int. J. Mol. Sci. 2022, 23(3), 1763; https://doi.org/10.3390/ijms23031763

Received: 13 October 2021 / Revised: 23 January 2022 / Accepted: 25 January 2022 / Published: 3 February 2022

(This article belongs to the Special Issue Calcium Channel Regulation in Cancer: Unravelling the Molecular Mechanisms beneath the Membrane)

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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. View Full-Text

Keywords: Orai1; store-operated Ca²⁺ entry; tyrosine kinase inhibitor; esophageal cancer; fluxes equations

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Chang, Y.; Funk, M.; Roy, S.; Stephenson, E.; Choi, S.; Kojouharov, H.V.; Chen, B.; Pan, Z. Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of Afatinib and RP4010 in Esophageal Cancer. Int. J. Mol. Sci. 2022, 23, 1763. https://doi.org/10.3390/ijms23031763

AMA Style

Chang Y, Funk M, Roy S, Stephenson E, Choi S, Kojouharov HV, Chen B, Pan Z. 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):1763. https://doi.org/10.3390/ijms23031763

Chicago/Turabian Style

Chang, Yan, Marah Funk, Souvik Roy, Elizabeth Stephenson, Sangyong Choi, Hristo V. Kojouharov, Benito Chen, and Zui Pan. 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, no. 3: 1763. https://doi.org/10.3390/ijms23031763

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