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.
Highlights
Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide
Previous studies have shown that several factors including genetic alteration impact success rate of patient-derived xenograft model establishment, whereas little is known about establishing Patient-derived cells (PDC) from advanced lung adenocarcinoma[23,24,25]
Our findings provided the evidence that both positive cytological diagnosis of malignancy (M+) and tumor colony formation (TCF+) were crucial to establishing PDCs from malignant effusions
Summary
Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. The most common molecular mechanisms of resistance are secondary mutations in kinase domains of the drug targets and activation of alternative pathways[3,4,5]. With advances in molecular profiling of acquired resistance, new therapeutic strategies, such as combination targeted therapies and next-generation TKIs, have been introduced to overcome the TKI resistance[1]. A limited panel of NSCLC cell lines harboring the EGFR mutation, ALK fusion, or ROS1 fusion is commercially-available. These models may exhibit different patterns of drug sensitivity likely due to lack of genetic complexity found in patients[6].
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