Abstract 2416: Activity of sunitinib for lung adenocarcinoma with RET rearrangement
Authors: June-Koo Lee, Soyeon Kim, Jong-Yeon Shin, Miso Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Jong-Il Kim, Dae Seog Heo, Jeong-Sun Seo, Se-Hoon Lee
Journal: Cancer Research (2015)

Abstract Background Oncogenic driver gene rearrangement involving RET proto-oncogene has been observed in about 1% of non-small-cell lung cancer (NSCLC). However, effective molecular targeted treatment for this population has not been established yet. In this study, we firstly identified and characterized a lung adenocarcinoma cell line harboring KIF5B-RET fusion. We also studied the activity of RET kinase inhibitor sunitinib in two patients with lung adenocarcinoma harboring RET rearrangement. Methods and Results SNU-2612A, a lung adenocarcinoma cell line harboring KIF5B-RET rearrangement, was derived from pleural effusion of a never-smoking male patient with lung adenocarcinoma. In vitro sensitivity of SNU-2612A and LC-2/ad, another lung adenocarcinoma cell line harboring CCDC6-RET fusion, to various RET kinase inhibitors was examined in immunoblotting and cell viability assay. SNU-2612A was relatively resistant to various RET kinase inhibitors including sunitinib, compared with LC-2/ad. Notably, gene expression analysis from transcriptome sequencing of the two cell lines showed higher expression of mesenchymal lineage-related genes in SNU-2612A, including FN1, VIM, ZEB1, SNAI1 and AXL. Phospho-receptor tyrosine kinase (RTK) array showed that phosphorylation of epidermal growth factor receptor (EGFR) was higher in SNU-2612A compared with LC-2/ad. We also investigated clinical activity of sunitinib, a multi-tyrosine kinase inhibitor that has activity on RET kinase in two heavily pretreated patients with lung adenocarcinoma harboring RET rearrangement (through an Emergency Investigational New Drug application, authorized by Ministry of Food and Drug Safety of Republic of Korea; Sunitinib was provided by Pfizer). They were all Asian, and never-smokers. RET rearrangement was confirmed by using fluorescence in situ hybridization. A 64-year-old male patient received sunitinib for 6th-line treatment. In this patient, sunitinib treatment resulted in long-term stabilization of disease; the patient was stable on sunitinib for 23 months. Another 53-year-old female patient received sunitinib for 5th-line treatment, showed initial mixed tumor response. However, her general medical condition was rapidly deteriorated and the treatment was discontinued (treatment duration = 1.7 months). Conclusions Sunitinib showed variable antitumor activity in cell line models and two pretreated patients with advanced NSCLC harboring RET rearrangement, which warrants further investigation. Citation Format: June-Koo Lee, Soyeon Kim, Jong-Yeon Shin, Miso Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Jong-Il Kim, Dae Seog Heo, Jeong-Sun Seo, Se-Hoon Lee. Activity of sunitinib for lung adenocarcinoma with RET rearrangement. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2416. doi:10.1158/1538-7445.AM2015-2416