Abstract B22: Can lung cancer with overexpression of RET-proto oncogene be a good candidate for vandetanib treatment?
Authors: Sunohara Mitsuhiro , Morita Shigeki , Kawakami Masanori , Watanabe Kousuke , Kage Hidenori , Amano Yousuke , Ishikawa Rie , Fukayama Masahisa , Nagase Takahide , Ohishi Nobuya , Takai Daiya 
Published: August 2014

1. Background: Vandetanib is a multikinase inhibitor of EGFR, VEGFR and RET, and is now clinically used for advanced medullary thyroid carcinoma treatment. KIF5B-RET fusion is reported to be novel oncogenic genomic translocation accounting for about 5% of lung cancers. However, overexpression of RET has not been well studied.

2. Material and methods:

a) We performed quantitative RT-PCR of 82 surgically resected adenocarcinomas. And using tissue micro array we performed immunohistochemistry (IHC) assay of 379 surgically resected lung cancer (151 squamous cell carcinomas(SCC), 210 adenocarcinomas, 6 large cell carcinomas, 6 pleomorphic carcinomas and 6 small cell carcinomas).

b) We performed a retrospective prognosis survey of 82 patients with surgically resected adenocarcinomas, stratifying based on RET overexpression and EGFR mutation.

c) Using lentiviral vectors, we generated RET-overexpressed A549, NCI-H23, and NCI-H1650. Then, we measured IC50 values for gefitinib and vandetanib in original cell lines, and RET-overexpressed cell lines using WST-8. Relative resistance index for gefitinib and vandetanib was calculated by dividing the IC50 value in RET-overexpressed cell by IC50 in original cell line.

3. Results:

a) RET was overexpressed in 4.6% of SCC, 17.1% of adenocarcinomas, and none of other histological type of lung cancers by using IHC assay. Quantitative RT-PCR also revealed that RET was overexpressed in 13.4% of adenocarcinomas.

c) Multivariate analysis showed that RET overexpression was more likely in patients with EGFR mutation (p=0.004, t-test). Among patients with EGFR mutation, RET-overexpression was a poor prognostic factor (p=0.001, Log Rank test).

c) In all the three cell lines, IC50 value for vandetanib was higher than that for gefitinib; the ratio was 1.25, 1.21 and 1.33, respectively. These data indicate that overexpression of RET leads to the development of resistance to gefitinib, and using vandetanib is a possible way to overcome the resistance.

4. Conclusions: RET overexpression is a poor prognostic factor among lung adenocarcinomas with EGFR mutation. Acquired resistance to gefitinib due to RET overexpression may explain this clinical data. This study indicated that instead of EGFR-TKI it is better to use vandetanib, which inhibits both EGFR and RET, for treating lung cancer with EGFR mutation and RET overexpression. To confirm this, a prospective randomized trial focusing on RET overexpression is needed.

Citation Format: Mitsuhiro Sunohara, Shigeki Morita, Masanori Kawakami, Kousuke Watanabe, Hidenori Kage, Yousuke Amano, Rie Ishikawa, Masahisa Fukayama, Takahide Nagase, Nobuya Ohishi, Daiya Takai. Can lung cancer with overexpression of RET-proto oncogene be a good candidate for vandetanib treatment? [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B22.