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Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers-Applications and Limitations
Shuta Ohara1, Kenichi Suda1, Tetsuya Mitsudomi1
1Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
Abstract:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are first-line drugs for lung cancers with activating EGFR mutations. Although first- and second-generation EGFR-TKIs were standard first-line treatments, acquired resistance (AR) to these drugs is almost inevitable. Cell line models have been widely used to explore the molecular mechanisms of AR to first- and second-generation EGFR-TKIs. Many research groups, including ours, have established AR cell lines that harbor the EGFR T790M secondary mutation, MET gene amplification, or epithelial-mesenchymal transition (EMT) features, which are all found in clinical specimens obtained from TKI-refractory lesions. Currently, many oncologists prescribe osimertinib, a third-generation EGFR-TKI that can overcome T790M-mediated resistance, as a first-line TKI. Although few clinical data are available about AR mechanisms that arise when osimertinib is used as a first-line therapy, many research groups have established cell lines with AR to osimertinib and have reported on their AR mechanisms. In this review, we summarize the findings on AR mechanisms against first-line osimertinib obtained from analyses of cell line models.
Insights
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is common in lung cancer. This review summarizes resistance mechanisms to first-line osimertinib (a third-generation EGFR-TKI) using cell line models.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are crucial in treating lung cancers with activating EGFR mutations.
- Acquired resistance (AR) to first- and second-generation EGFR-TKIs is a significant clinical challenge, often involving mechanisms like the T790M mutation or MET amplification.
- Osimertinib, a third-generation EGFR-TKI, is now a first-line treatment, but understanding its resistance mechanisms is critical.
Purpose of the Study:
- To review and summarize the known mechanisms of acquired resistance (AR) to first-line osimertinib.
- To consolidate findings from cell line models that investigate AR to osimertinib.
- To provide insights into the molecular basis of osimertinib resistance for future therapeutic strategies.
Main Methods:
- Analysis of established cell line models with acquired resistance to osimertinib.
- Review of published research on AR mechanisms against first-line osimertinib.
- Correlation of cell line findings with known clinical resistance patterns in EGFR-mutated lung cancer.
Main Results:
- Cell line models have identified various AR mechanisms to osimertinib, including bypass signaling pathways and cellular plasticity.
- These models mimic resistance features observed in clinical settings, such as specific mutations or altered cellular phenotypes.
- The T790M mutation, while overcome by osimertinib, can still play a role in complex resistance networks.
Conclusions:
- Cell line models are valuable tools for dissecting the complex mechanisms of acquired resistance to first-line osimertinib.
- Understanding these resistance mechanisms is essential for developing novel therapeutic approaches to overcome osimertinib failure in EGFR-mutated lung cancer.
- Further research is needed to translate these findings into effective clinical interventions.
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