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Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of
Yan Chang1, Marah Funk2, Souvik Roy2
1College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, USA.
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.
Insights
Combining afatinib and RP4010 shows synergistic anticancer effects in esophageal cancer. Mathematical simulations guided the identification of optimal drug ratios, improving treatment strategies.
Area of Science:
- Oncology
- Biochemistry
- Computational Biology
Background:
- Dysregulated calcium (Ca2+) signaling is a target for cancer chemotherapy.
- Store-operated Ca2+ entry (SOCE) blockers like RP4010 show promise for esophageal cancer.
- Afatinib, a tyrosine kinase inhibitor (TKI), is approved for EGFR mutation-positive cancers, including esophageal cancer.
Purpose of the Study:
- To evaluate the combined anticancer effects of afatinib and RP4010 on esophageal cancer cells.
- To investigate the impact of afatinib and RP4010 on intracellular Ca2+ oscillations using experimental and mathematical approaches.
- To determine if mathematical simulations can guide the optimal ratio for combined therapy.
Main Methods:
- Utilized KYSE-150 human esophageal squamous cell carcinoma cell line.
- Employed experimental measurements of intracellular Ca2+ oscillations and cell proliferation.
- Developed and validated mathematical models to simulate Ca2+ dynamics under drug treatment.
Main Results:
- Mathematical simulations accurately reflected experimental data for afatinib and RP4010, individually and in combination.
- The study identified an optimal ratio of afatinib and RP4010 for combined treatment based on simulation guidance.
- Combined treatment demonstrated synergistic anticancer effects, confirmed by Ca2+ measurements and reduced cell proliferation.
Conclusions:
- A combination of afatinib and RP4010 exhibits synergistic anticancer activity against esophageal cancer.
- Intracellular Ca2+ dynamic-based mathematical modeling is a valuable tool for optimizing combined targeted therapy drug evaluation.
- This approach offers a rapid and cost-effective method for assessing combination drug therapies.
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