Identification of CCDC6-RET Fusion in the Human Lung Adenocarcinoma Cell Line, LC-2/ad

Matsubara, Daisuke; Kanai, Yoshihiko; Ishikawa, Shumpei; Ohara, Shiori; Yoshimoto, Taichiro; Sakatani, Takashi; Oguni, Sachiko; Tamura, Tomoko; Kataoka, Hiroaki; Endo, Shunsuke; Murakami, Yoshinori; Aburatani, Hiroyuki; Fukayama, Masashi; Niki, Toshiro

doi:10.1097/jto.0b013e3182721ed1

Cited by 85 publications

(75 citation statements)

References 15 publications

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“…No RET/PTC1 fusion or CCDC6 mutations have been reported in these cell lines. 23 Olaparib was provided by Astra Zeneca (AZD2281) and cisplatinum was form SIGMA-Aldrich.…”

Section: Cell Lines Drugs and Chemicalsmentioning

confidence: 99%

New therapeutic perspectives in CCDC6 deficient lung cancer cells

Morra

Luise

Visconti

et al. 2014

Intl Journal of Cancer

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Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coildomain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p 0.02) and negatively correlated to the disease free survival (p 0.01) and the overall survival (p 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC.

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“…No RET/PTC1 fusion or CCDC6 mutations have been reported in these cell lines. 23 Olaparib was provided by Astra Zeneca (AZD2281) and cisplatinum was form SIGMA-Aldrich.…”

Section: Cell Lines Drugs and Chemicalsmentioning

confidence: 99%

New therapeutic perspectives in CCDC6 deficient lung cancer cells

Morra

Luise

Visconti

et al. 2014

Intl Journal of Cancer

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“…15 In contrast to thyroid cancer where CCDC6 and NCOA4 are more common upstream partner genes, KIF5B is the most common upstream fusion partner of RET in NSCLC. [16][17][18][19][20][21] Independent investigators have demonstrated that multikinase RET inhibitors, such as cabozantinib and vandetanib, are active in vitro and in vivo against various RET-rearranged lung cancer models. [22][23][24] Furthermore, Drilon et al 25 previously reported the activity of cabozantinib in patients with RET-rearranged lung cancers in a phase II trial.…”

Section: Introductionmentioning

confidence: 99%

Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry

Gautschi

Milia

Filleron

et al. 2017

JCO

292

242

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In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RETrearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. MethodsA global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or nextgeneration sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. ResultsBy April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). ConclusionAvailable multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

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“…Silencing of RET expression by siRNA targeting RET significantly decreased phosphorylation of ERK1/2, a key molecule of RET downstream signaling, and cell viability in LC-2/ad cells (14,15). These results indicate that CCDC6-RET plays an important role in the proliferation and survival of LC-2/ad cells.…”

Section: Dovitinib Inhibits Ret Kinase Activitymentioning

confidence: 49%

“…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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Identification of CCDC6-RET Fusion in the Human Lung Adenocarcinoma Cell Line, LC-2/ad

Cited by 85 publications

References 15 publications

New therapeutic perspectives in CCDC6 deficient lung cancer cells

New therapeutic perspectives in CCDC6 deficient lung cancer cells

Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry

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

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