Abstract
AbstractLung adenocarcinoma (LUAD) is associated with a low survival rate at advanced stages. Although the development of targeted therapies has improved outcomes in LUAD patients with identified and specific genetic alterations, such as activating mutations on the epidermal growth factor receptor gene (EGFR), the emergence of tumor resistance eventually occurs in all patients and this is driving the development of new therapies. In this paper, we present the In Silico EGFR-mutant LUAD (ISELA) model that links LUAD patients’ individual characteristics, including tumor genetic heterogeneity, to tumor size evolution and tumor progression over time under first generation EGFR tyrosine kinase inhibitor gefitinib. This translational mechanistic model gathers extensive knowledge on LUAD and was calibrated on multiple scales, including in vitro, human tumor xenograft mouse and human, reproducing more than 90% of the experimental data identified. Moreover, with 98.5% coverage and 99.4% negative logrank tests, the model accurately reproduced the time to progression from the Lux-Lung 7 clinical trial, which was unused in calibration, thus supporting the model high predictive value. This knowledge-based mechanistic model could be a valuable tool in the development of new therapies targeting EGFR-mutant LUAD as a foundation for the generation of synthetic control arms.
Publisher
Springer Science and Business Media LLC
Subject
Applied Mathematics,Computer Science Applications,Drug Discovery,General Biochemistry, Genetics and Molecular Biology,Modeling and Simulation
Reference56 articles.
1. Bradley, S. H., Kennedy, M. P. T. & Neal, R. D. Recognising lung cancer in primary care. Adv. Ther. 36, 19–30 (2018).
2. Wang, H. et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the global burden of disease study 2015. Lancet 388, 1459–1544 (2016).
3. Maity, S., Pai, K. S. R. & Nayak, Y. Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance. Pharmacol. Rep. 72, 799–813 (2020).
4. Planchard, D. et al. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv192–iv237 (2018).
5. NCCN. Non-Small Cell Lung Cancer Metastatic. NCCN Guidelines for Patients. https://www.nccn.org/patients/guidelines/content/PDF/lung-metastatic-patient.pdf (2022).
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