Ponatinib (AP24534) Is a Novel Potent Inhibitor of Oncogenic RET Mutants Associated With Thyroid Cancer

Falco, Valentina De; Buonocore, Preziosa; Magesh, Muthu; Torregrossa, Liborio; Basolo, Fulvio; Billaud, Marc; Gozgit, Joseph M.; Carlomagno, Francesca; Santoro, Massimo

doi:10.1210/jc.2012-2672

Cited by 88 publications

(72 citation statements)

References 35 publications

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“…The following primary antibodies were used for western blotting (all from Cell Signaling Technology, except where indicated): anti-FGFR2 (1:1000); anti-ALK; anti-Trk-A (Santa Cruz; 1:500); anti-Trk (Santa Cruz; 1:500); anti-cKIT (1:1,000); anti-PDGFRA (1:1,000); anti-phospho-p44/42 ERK (Thr202/Tyr204; 1:1,000); anti-p44/42 ERK (1:1,000); anti-phospho-MEK1/2 (Ser217/221; 1:1,000); anti-MEK1/2 (1:1,000); anti-phospho AKT (Ser473; 1:1,000); anti-AKT (1:1,000); anti-PARP (1:1,000); anti-actin (Santa Cruz; 1:3,000); anti-vinculin (Millipore; 1:5,000); anti-PTEN (1:1,000). Anti-RET antibody 45 (1:500) was kindly provided by Professor Massimo Santoro (Federico II, Naples). The full-length western blot membranes are shown in Supplementary Figs 9-13.…”

Section: Articlementioning

confidence: 99%

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

et al. 2015

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The development of molecularly targeted anticancer agents relies on large panels of tumourspecific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.

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Section: Articlementioning

confidence: 99%

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

et al. 2015

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“…Some compounds were isolated that exerted potent RET inhibition. They include vandetanib (ZD6474), sorafenib (BAY 43-9006), sunitinib (SU11248), cabozantinib (XL184), lenvatinib (E7080), and ponatinib (AP24534) (Carlomagno et al 2002(Carlomagno et al , 2006Kim et al 2006;Verbeek et al 2011;De Falco et al 2013). These compounds are multitargeted, being able to inhibit RET and also additional kinases.…”

Section: Ret Kinase Inhibitorsmentioning

confidence: 99%

Central Role of RET in Thyroid Cancer

Santoro

Carlomagno

2013

Cold Spring Harbor Perspectives in Biology

102

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“…Recently, preliminary clinical activity of a RET inhibitor, cabozanitnib, has been reported in patients with NSCLC harbouring RET rearrangement 84. Another TKI, ponatinib, recently approved for refractory chronic myelogenous leukaemia has also demonstrated excellent in vitro RET inhibitory activity 85. Clinical trials with multiple RET inhibitors in RET -rearranged NSCLC are ongoing or being planned.…”

Section: Introductionmentioning

confidence: 99%

Lung cancer in never-smokers. Does smoking history matter in the era of molecular diagnostics and targeted therapy?

Ou¹

2013

J Clin Pathol

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Lung cancer in never-smokers was recognised as a distinct clinical entity around the mid-2000s because these patients tended to be Asian women and diagnosed at a younger age with a preponderance of adenocarcinoma and better survival outcome despite a more advanced stage of presentation. It was soon discovered that lung cancer in never-smokers had a higher prevalence of activating EGFR mutations and we tend to classify lung cancer by smoking status for screening purpose. With the discoveries of many actionable driver mutations such as activating EGFR mutations and ALK rearrangement in adenocarcinoma of the lung we have switched to classifying non-small cell lung cancer into different individual molecular subgroups based on the presence of a dominant driver mutation. Although many actionable driver mutations are found in never-smokers with adenocarcinoma, this review will summarise that a substantial proportion of patients with these actionable driver mutations had a previous smoking history. Alternatively among the driver mutations that are associated with smoking history, a fair amount of these patients were never-smokers. Thus smoking status should not be used as a screen strategy for identifying driver mutations in clinical practice. Finally smoking history may have predictive and/or prognostic significance within individual molecular subgroups and identifying the difference according to smoking history may help optimise future targeted therapy.

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Ponatinib (AP24534) Is a Novel Potent Inhibitor of Oncogenic RET Mutants Associated With Thyroid Cancer

Abstract: Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma.

Cited by 88 publications

References 35 publications

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

Central Role of RET in Thyroid Cancer

Lung cancer in never-smokers. Does smoking history matter in the era of molecular diagnostics and targeted therapy?

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