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

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

doi:10.3390/ijms23031763

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.

Highlights

Esophageal cancer (EC) is the sixth leading cause of cancer mortality worldwide [1]
Since tyrosine kinase inhibitor (TKI) can alter intracellular Ca2+ dynamics through epidermal growth factor receptor (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
Afatinib is an effective TKI for EGFR/ERBB2; we suspected that these esophageal squamous cell carcinoma (ESCC) cells should be sensitive to afatinib

Summary

Introduction

Esophageal cancer (EC) is the sixth leading cause of cancer mortality worldwide [1]. In 2021, in the United States alone, there is an estimated number of 19,260 new cases of EC and 15,530 deaths from EC (www.seer.cancer.gov/statfacts, accessed on 24 January 2022). Two main types of EC are distinguished by different etiological and pathological characteristics: esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). While EAC is more prevalent in the USA, ESCC predominates among Asians and male African Americans [2]. Both cancers remain asymptomatic; patients are usually diagnosed at relatively late stages, with an overall 5-year survival rate of below 20%, according to the SEER Cancer Statistics review [3]. In recent years, targeting dysregulated Ca2+ signaling in cancer cells has become an active research area to develop new chemotherapy drugs [4]

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