Alectinib Shows Potent Antitumor Activity against<i>RET</i>-Rearranged Non–Small Cell Lung Cancer

Kodama, Tatsushi; Tsukaguchi, Toshiyuki; Satoh, Yasuko; Yoshida, Miyuki; Watanabe, Yoshiaki; Kondoh, Osamu; Sakamoto, Hiroshi

doi:10.1158/1535-7163.mct-14-0274

Cited by 141 publications

(121 citation statements)

References 43 publications

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“…Vandetanib, an inhibitor of VEGFR, EGFR, and RET, showed a dramatic response in a patients with advanced RET fusion-positive LADC (16). Moreover, alectinib (CH5424802), which has been known to be a selective inhibitor of ALK, showed antitumor activity against RET fusiondriven LADC models by inhibiting oncogenic RET fusion signaling (23). Our data support the inclusion of dovitinib in the therapeutic armamentarium of targeted agents currently being tested for RET fusion-positive LADC.…”

Section: Discussionsupporting

confidence: 66%

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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Section: Discussionsupporting

confidence: 66%

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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“…It was subsequently shown to be an effective RET inhibitor in vitro and in vivo (Kodama et al 2014). Although alectinib is not quite as potent against RET as it is against ALK, the compound is active on most RET mutants tested and shows very good selectivity for RET vs VEGFR, which may be a competitive advantage over competing drugs.…”

Section: Investigational Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

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“…In several pre-clinical studies, the growth of RET fusion-positive cells could be inhibited by the multitargeted tyrosine kinase inhibitors (TKIs) with activity against the RET kinase, like sunitinib, sorafenib, vandetanib and alectinib. 10,11,16,17 While in 3 independent phase II trials, RET inhibitors including cabozantinib and vandetanib were used to treat a total of 7 RET fusion-positive patients of lung adenocarcinoma. 14,18,19 As a result, 4 had confirmed partial responses and 3 had prolonged stable disease, indicating the therapeutic potential of RET inhibitors as targeted drugs tailored for RET fusion-positive patients.…”

Section: Introductionmentioning

confidence: 99%

The RET fusion gene and its correlation with demographic and clinicopathological features of non-small cell lung cancer: a meta-analysis

Chen

Wang

Xie

et al. 2015

Cancer Biology & Therapy

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(2015) The RET fusion gene and its correlation with demographic and clinicopathological features of non-small cell lung cancer: a meta-analysis, Cancer Biology & Therapy, 16:7, 1019-1028, DOI: 10.1080/15384047.2015 Purpose. The RET fusion gene is a novel oncogene observed in a subset of NSCLC in recent years. Nevertheless, the results of epidemiological studies concerning the gene remain unclear. Thus, a meta-analysis was conducted to evaluate the correlation of RET fusion gene with demographic and clinicopathological features of NSCLC. Methods. PubMed, Embase, and Web of Science databases were searched to identify eligible studies. The association of RET fusion gene occurrence with gender, age, smoking status, histology type and tumor stage were analyzed in metaanalysis. Subgroup analysis according to patients' location (Asian and non-Asian) was also conducted. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the correlation. Results. Nine studies with a total of 6,899 NSCLC patients met the inclusion criteria. A total of 84 patients with RET fusion gene were detected. The RET fusion gene was identified at significantly higher frequencies in female (OR D 0.55, 95%CI D 0.35-0.85) than male patients and in young (<60 ) patients (OR D 0.43, 95%CI D 0.19-0.99) than old patients ( 60 ), particularly in patients from Asian. A significant higher frequency was also identified in non-smokers (OR D 0.28, 95% CI D 0.16-0.49), and in patients with lung adenocarcinomas (OR D 3.59, 95%CI D 1.50-8.56). Additionally, no association between RET fusion gene and the TNM stage of tumor was observed. Conclusion. RET fusion gene occurred predominantly in Asian females with younger age, in non-smokers, and in lung adenocarcinomas patients. This subset of NSCLC patients might be good candidates for personalized diagnostic and therapeutic approaches.

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Alectinib Shows Potent Antitumor Activity againstRET-Rearranged Non–Small Cell Lung Cancer

Cited by 141 publications

References 43 publications

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

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

Novel targeted therapeutics for MEN2

The RET fusion gene and its correlation with demographic and clinicopathological features of non-small cell lung cancer: a meta-analysis

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