KIF5B-RET fusions in lung adenocarcinoma

Kohno, Takashi; Ichikawa, Hitoshi; Totoki, Yasushi; Yasuda, Kazuki; Hara, Masaki; Nammo, Takao; Sanada, Hiromi; Tsuta, Koji; Furuta, Koh; Shimada, Yôko; Iwakawa, Reika; Ogiwara, Hideaki; Oike, Takahiro; Enari, Masato; Schetter, Aaron J.; Okayama, Hirokazu; Haugen, Aage; Skaug, Vidar; Chiku, Suenori; Yamanaka, Itaru; Arai, Yasuhito; Watanabe, Shun‐ichi; Sekine, Ikuo; Ogawa, Seishi; Harris, Curtis C.; Tsuda, Hitoshi; Yoshida, Teruhiko; Yokota, Jun; Shibata, Tatsuhiro

doi:10.1038/nm.2644

Cited by 749 publications

(654 citation statements)

References 18 publications

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“…62,64,65 RET fusion occurs more frequently in never smokers than ever smokers. 37,62,64,66,72 Patients with RET fusion harboring tumors are usually younger than patients with an EGFR mutation and have an equal gender distribution. 67 RET fusion proteins have been detected in adenocarcinoma 37,62,64 and in adenosquamous carcinoma.…”

Section: Expert Consensus Opinionmentioning

confidence: 98%

“…As with ALK and ROS1 rearrangements, RET is activated by rearrangements that fuse the tyrosine kinase domain of RET with coiled-coil dimerization domains of one of a variety of recurring partner genes, including KIF5B (the most common, at 90%), 64 72 RET rearrangement is mutually exclusive with aberrations in EGFR, KRAS, ALK, HER2, and BRAF in lung cancer. 62,64,65 RET fusion occurs more frequently in never smokers than ever smokers.…”

Section: Expert Consensus Opinionmentioning

confidence: 99%

“…37,62,64,66,72 Patients with RET fusion harboring tumors are usually younger than patients with an EGFR mutation and have an equal gender distribution. 67 RET fusion proteins have been detected in adenocarcinoma 37,62,64 and in adenosquamous carcinoma. 62 Histologic subtypes in adenocarcinomas include those with mucinous/signet ring cells and those with a cribriform 37,62,65 or solid growth pattern.…”

Section: Expert Consensus Opinionmentioning

confidence: 99%

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Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Aung

Donald

Ellison

et al. 2014

The Journal of Molecular Diagnostics

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Context: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. Objective: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. Design: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. Results: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. Conclusions: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of

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Section: Expert Consensus Opinionmentioning

confidence: 98%

Section: Expert Consensus Opinionmentioning

confidence: 99%

Section: Expert Consensus Opinionmentioning

confidence: 99%

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Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Aung

Donald

Ellison

et al. 2014

The Journal of Molecular Diagnostics

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“…Recently, RET rearrangement, specifically fusion, has emerged as a new molecular subtype in LADC (6,7). The prevalence of RET fusions has been estimated approximately 1.2% to 2.0% in LADC (6)(7)(8)(9)(10)(11). Several RET fusions have been identified in LADC, including kinesin family member 5B (KIF5B)-RET, coiled-coil domain containing 6 (CCDC6)-RET, tripartite motif-containing 33 (TRIM33)-RET, and nuclear receptor coactivator 4 (NCOA4)-RET.…”

Section: Introductionmentioning

confidence: 99%

“…Small-molecule tyrosine kinase inhibitors (TKI), including vandetanib, sunitinib, and sorafenib, effectively inhibited RET fusion-positive LADC in preclinical models (7,8,10,14,15). Therefore, several clinical trials of RET inhibitors are ongoing in RET fusion-positive LADC.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma

Kang

Jang

Sohn

et al. 2015

Molecular Cancer Therapeutics

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RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G 0 -G 1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.

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Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs

Kris

Johnson

Berry

et al. 2014

JAMA

1,468

1,136

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IMPORTANCE Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. OBJECTIVES To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. DESIGN, SETTING, AND PARTICIPANTS From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. INTERVENTIONS Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. MAIN OUTCOMES AND MEASURES Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. RESULTS From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score–adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006). CONCLUSIONS AND RELEVANCE Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.

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KIF5B-RET fusions in lung adenocarcinoma

Cited by 749 publications

References 18 publications

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma

Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs

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