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Role of Orai3 in the Pathophysiology of Cancer
 
 
Article

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

1
College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, USA
2
Department of Mathematics, The University of Texas at Arlington, Arlington, TX 76019, USA
3
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
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 Orai1; store-operated Ca2+ entry; tyrosine kinase inhibitor; esophageal cancer; fluxes equations
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MDPI and ACS Style

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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