Abstract
The most common driver mutations in lung adenocarcinoma occur in the EGFR gene. Gefitinib, an EGFR tyrosine kinase inhibitor, is an effective therapy for lung adenocarcinoma with EGFR mutations. However, resistant tumors inevitably arise. One of the mechanisms conferring gefitinib resistance is the amplification of the MET gene, which is observed in 5–22% of all cases. A previous study suggested that MET overexpression may cause gefitinib resistance through ErbB3, and most likely through the formation of EGFR-ErbB3 heterodimers. In this study, we focused on the dimer formation of EGFR and ErbB3 in lung adenocarcinoma cells and built a mathematical model using ordinary differential equations. To simulate the dimerization process of EGFR and ErbB3, we determined the molecular concentrations of each on the cell surface by flow cytometry and estimated unknown reaction constants by dimensional analysis. Our mathematical model would provide a quantitative understanding of dimer formation, one which cannot be obtained by a molecular biology methods.
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References
Hynes, N.E., Lane, H.A.: ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer 5, 341–354 (2005)
Sharma, S.V., Bell, D.W., Settleman, J., Haber, D.A.: Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 7, 169–181 (2007)
Baselga, J., Swain, S.M.: Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 9, 463–475 (2009)
Rotow, J., Bivona, T.G.: Understanding and targeting resistance mechanisms in NSCLC. Nat. Rev. Cancer 17, 637–658 (2017)
Engelman, J.A., Zejnullahu, K., Mitsudomi, T., et al.: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007)
Ito, T., Kumagai, Y., Itano, K., et al.: Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification. Biochem. Biophys. Res. Commun. 511, 544–550 (2019)
Serke, S., van Lessen, A., Huhn, D.: Quantitative fluorescence flow cytometry: a comparison of the three techniques for direct and indirect immunofluorescence. Cytometry 33, 179–187 (1998)
Novy, Z., Barta, P., Mandikova, J., et al.: A comparison of in vitro methods for determining the membrane receptor expression in cell lines. Nucl. Med. Biol. 39, 893–896 (2012)
Macdonald, J.L., Pike, L.J.: Heterogeneity in EGF-binding affinities arises from negative cooperativity in an aggregating system. Proc. Natl. Acad. Sci. U.S.A. 105, 112–117 (2008)
Teramura, Y., Ichinose, J., Takagi, H., et al.: Single-molecule analysis of epidermal growth factor binding on the surface of living cells. EMBO J. 25, 4215–4222 (2006)
Low-Nam, S.T., Lidke, K.A., Cutler, P.J., et al.: ErbB1 dimerization is promoted by domain co-confinement and stabilized by ligand binding. Nat. Struct. Mol. Biol. 18, 1244–1249 (2011)
Hiroshima, M., Saeki, Y., Okada-Hatakeyama, M., Sako, Y.: Dynamically varying interactions between heregulin and ErbB proteins detected by single-molecule analysis in living cells. Proc. Natl. Acad. Sci. U.S.A. 109, 13984–13989 (2012)
Steinkamp, M.P., Low-Nam, S.T., Yang, S., et al.: ErbB3 is an active tyrosine kinase capable of homo- and heterointeractions. Mol. Cell. Biol. 34, 965–977 (2014)
Itano, K., Ito, T., Kawasaki, S., et al.: Mathematical modeling and analysis of ErbB3 and EGFR dimerization process for the gefitinib resistance. JSIAM Lett. 10, 33–36 (2018)
Lenferink, A.E., Pinkas-Kramarski, R., van der Poll, M.L., et al.: Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J. 17, 3385–3397 (1998)
Schoeberl, B., Faber, A.C., Li, D., et al.: An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res. 70, 2485–2494 (2010)
Byrne, P.O., Hristova, K., Leahy, D.J.: EGFR forms ligand-independent oligomers that are distinct from the active state. J. Biol. Chem. 295, 13353–13362 (2020)
Endres, N.F., Das, R., Smith, A.W., et al.: Conformational coupling across the plasma membrane in activation of the EGF receptor. Cell 152, 543–556 (2013)
Acknowledgments
We thank Dr. Yuki Kumagai for her technical assistance and also acknowledge Dr. Keiko Itano and Dr. Shuji Kawasaki for fruitful discussions. This work was supported by JSPS KAKENHI Grant Numbers 17H05993 and 20H05028 to TI and Core-to-Core Program, A. Advanced Research Networks to TS.
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Ito, T., Suzuki, T., Murakami, Y. (2021). Mathematical Modeling of the Dimerization of EGFR and ErbB3 in Lung Adenocarcinoma. In: Suzuki, T., Poignard, C., Chaplain, M., Quaranta, V. (eds) Methods of Mathematical Oncology. MMDS 2020. Springer Proceedings in Mathematics & Statistics, vol 370. Springer, Singapore. https://doi.org/10.1007/978-981-16-4866-3_12
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DOI: https://doi.org/10.1007/978-981-16-4866-3_12
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