Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma

Seok Young Kim, Ji Yeon Lee, Dong Hwi Kim, Hyeong Seok Joo, Mi Ran Yun, Dongmin Jung, Jiyeon Yun, Seong Gu Heo, Beung Chul Ahn, Chae Won Park, Kyoung Ho Pyo, You Jin Chun, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho

Research output: Contribution to journalArticle

Abstract

Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We generated 23 PDCs from 96 malignant effusions of 77 patients with advanced lung adenocarcinoma. Clinical and experimental factors were reviewed to identify determinants for PDC establishment. PDCs were characterized by driver mutations and in vitro sensitivity to targeted therapies. Seven PDCs were analyzed by whole-exome sequencing. PDCs were established at a success rate of 24.0%. Utilizing cytological diagnosis and tumor colony formation can improve the success rate upto 48.8%. In vitro response to a tyrosine kinase inhibitor (TKI) in PDC reflected patient treatment response and contributed to identifying effective therapies. Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.

Original languageEnglish
Article number19909
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

All Science Journal Classification (ASJC) codes

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    Kim, S. Y., Lee, J. Y., Kim, D. H., Joo, H. S., Yun, M. R., Jung, D., Yun, J., Heo, S. G., Ahn, B. C., Park, C. W., Pyo, K. H., Chun, Y. J., Hong, M. H., Kim, H. R., & Cho, B. C. (2019). Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma. Scientific reports, 9(1), [19909]. https://doi.org/10.1038/s41598-019-56356-4