RET fusion gene: translation to personalized lung cancer therapy

Abstract

Development of lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, depends in many cases on the activation of "driver" oncogenes such as KRAS, epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK). Inhibitors that target the EGFR and ALK tyrosine kinases show therapeutic effects against LADCs containing EGFR gene mutations and ALK gene fusions, respectively. Recently, we and others identified the RET fusion gene as a new targetable driver gene in LADC. The RET fusions occur in 1-2% of LADCs. Existing US Food and Drug Administration-approved inhibitors of RET tyrosine kinase show promising therapeutic effects both in vitro and in vivo, as well as in a few patients. Clinical trials are underway to investigate the therapeutic effects of RET tyrosine kinase inhibitors, such as vandetanib (ZD6474) and cabozantinib (XL184), in patients with RET fusion-positive non-small-cell lung cancer.

Figure 1

Pie chart showing the fraction of Japanese lung adenocarcinoma patients that harbor “driver” gene mutations. Surgical specimens from 319 stage I–II lung adenocarcinomas deposited in the National Cancer Center Biobank (Japan) were subjected to analysis. The EGFR,KRAS,BRAF, and HER2 mutations (mut) were examined using the high resolution melting method, whereas ALK,ROS1 and RET fusions were examined by RT‐PCR.12, 31 The protocol for this research project has been approved by the institutional review board of the National Cancer Center.

Figure 2

Involvement of the RET gene in lung and thyroid carcinogenesis and in a developmental disorder. Upper panel, somatic inversion in chromosome 10 results in KIF5B–RET fusions. The RET fusion protein has constitutive tyrosine (Tyr) kinase activity, representing a gain‐of‐function alteration. Lower panel, RET alterations in other diseases. A germline gain‐of‐function mutation of RET drives thyroid carcinogenesis in patients with multiple endocrine neoplasia type 2 (MEN2). Somatic gain‐of‐function mutation and translocation of RET cause medullary and papillary thyroid cancers, respectively. Germline loss‐of‐function RET mutations cause Hirschsprung's disease, a hereditary disorder characterized by the absence of enteric ganglia in variable segments of intestine. FMTC, familial medullary thyroid carcinoma; P, phosphorylation; X, inactivating mutation.

Figure 3

Strategies used to identify RET fusion in lung adenocarcinoma. Four different methods were used to identify novel oncogenic fusions in lung adenocarcinomas.10, 11, 12, 13

Figure 4

Consolidated Standards of Reporting Trials diagram of the Lung Cancer Genomic Screening Project for Individualized Medicine in Japan (LC‐SCRUM) and the Lung Cancer with RET rearrangement (LURET) study in Japan. The LC‐SCRUM screen identified 17 RET fusion‐positive cases from non‐squamous non‐small‐cell lung carcinoma cases without epidermal growth factor receptor (EGFR) mutations (mut). The RET fusion‐positive cases are defined as being positive in both RT‐PCR and subsequent FISH tests. Representative pictures of these tests are shown. Fusion‐positive cases were treated with vandetanib in the LURET study. Ch10, chromosome 10; FFPE, formalin‐fixed paraffin‐embedded.