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

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.

Afatinib triggers a Ni2+‐resistant Ca2+ influx pathway in A549 non‐small cell lung cancer cells

“…A few studies have demonstrated that afatinib may suppress cancer cell growth by inhibiting, rather than promoting (as shown in our present study) Ca 2+ signaling. Afatinib, RP4010 (an inhibitor of store‐operated Ca 2+ entry), or a combination of the two agents, could inhibit Ca 2+ oscillations and decrease viability of human esophageal carcinoma KYSE‐150 cells [19]. In PC‐9/GR cells 9 (NSCLC with EGFR T790M mutation), afatinib treatment suppressed store‐operated Ca 2+ entry and decreased cell proliferation [20].…”

An evolutionary differential game for regulating the role of monoclonal antibodies in treating signalling pathways in oesophageal cancer

“…Oesophageal cancer (OC) ranks as the sixth most prevalent cause of cancer-related mortality on a global scale [ 1 ]. The signalling pathways within OC, encompassing monovalent ligands like epidermal growth factor (EGF) receptor and the complex receptor formed by the combination of the epidermal growth factor receptor (EGFR) and EGF, are of utmost importance in regulating cellular viability, proliferation and differentiation [ 2 ]. Genetic mutations frequently cause dysregulation of cancer cell signalling pathways, which in turn causes cancer cells to become resistant to treatment [ 3 ].…”