Abstract
The emergence of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd-generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after front-line osimertinib treatment failure because of a secondary mutation. We also established acquired resistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however, it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020-resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial-to-mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.
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MDPI and ACS Style
Fukuda, S.; Suda, K.; Hamada, A.; Oiki, H.; Ohara, S.; Ito, M.; Soh, J.; Mitsudomi, T.; Tsutani, Y.
Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms—An In Vitro Study. Biomedicines 2024, 12, 1412.
https://doi.org/10.3390/biomedicines12071412
AMA Style
Fukuda S, Suda K, Hamada A, Oiki H, Ohara S, Ito M, Soh J, Mitsudomi T, Tsutani Y.
Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms—An In Vitro Study. Biomedicines. 2024; 12(7):1412.
https://doi.org/10.3390/biomedicines12071412
Chicago/Turabian Style
Fukuda, Shota, Kenichi Suda, Akira Hamada, Hana Oiki, Shuta Ohara, Masaoki Ito, Junichi Soh, Tetsuya Mitsudomi, and Yasuhiro Tsutani.
2024. "Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms—An In Vitro Study" Biomedicines 12, no. 7: 1412.
https://doi.org/10.3390/biomedicines12071412
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