Co-existence of positive MET FISH status with EGFR mutations signifies poor prognosis in lung adenocarcinoma patients

Tanaka, Aya; Sueoka‐Aragane, Naoko; Nakamura, Tomomi; Takeda, Yuji; Mitsuoka, Masahiro; Yamasaki, Fumio; Hayashi, Shinichiro; Sueoka, Eisaburo; Kimura, Shinya

doi:10.1016/j.lungcan.2011.06.004

Cited by 58 publications

(44 citation statements)

References 41 publications

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“…Interestingly, none of the other 22 RTK ligands tested were able to rescue BRAF -mutated melanoma cells from the BRAF inhibitor. In accordance with what was described by Wilson and colleagues ( 52 ) among all the evaluated ligands, only HGF was able to simultaneously and effi ciently activate both the PI3K/AKT and MAPK pathways. These data suggest that a combined anti-RAF and anti-MET/HGF therapy might represent a useful option in patients affected by RAFmutated tumors, such as melanomas, colon cancer, and glioblastomas.…”

Section: Melanomasupporting

confidence: 87%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

Corso

Giordano

2013

Cancer Discovery

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Targeted therapies have opened new perspectives in clinical oncology. However, clinicians have observed a lack of response in a relevant percentage of patients and frequent relapse in patients who initially respond. Therefore, a compelling challenge is to identify mechanisms underlying resistance and strategies to circumvent these hurdles. A growing body of evidence indicates that MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), is frequently implicated in resistance to targeted therapies. In this review, we highlight cell-autonomous and non-cell-autonomous mechanisms through which MET drives resistance, and we discuss some unsolved issues related to the selection of patients who could benefi t from combined therapies. Signifi cance:Resistance is, at present, the major limitation to the effi cacy of targeted therapies. Inappropriate MET activation is very frequently implicated in the onset of primary and secondary resistance to these therapies. Deciphering the role of the HGF/MET axis in resistance to different drugs could guide the design of new clinical trials based on combinatorial therapies, and it might help to overcome, or possibly prevent, the onset of resistance. Cancer Discov; 3(9);

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Section: Melanomasupporting

confidence: 87%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

Corso

Giordano

2013

Cancer Discovery

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“…MET gene amplification was reported in subsets of patients, including esophagogastric cancer (11)(12)(13), colorectal cancer (14), head and neck squamous cell cancer (15), glioblastoma (16) and EGFR-na€ ve non-small cell lung cancer (NSCLC; refs. 17,18). MET gene amplification was also reported in 12% of patients with NSCLC with acquired resistance to EGFR kinase inhibitors (19)(20)(21)(22)(23)(24) and in 40% (4 of 7 patients) of cetuximab or panitumumab-resistant patients with colorectal cancer (25).…”

Section: Introductionmentioning

confidence: 96%

The Selective Intravenous Inhibitor of the MET Tyrosine Kinase SAR125844 Inhibits Tumor Growth inMET-Amplified Cancer

Égile

Kenigsberg

Delaisi

et al. 2015

Molecular Cancer Therapeutics

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Activation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. SAR125844 displayed nanomolar activity against the wild-type kinase (IC 50 value of 4.2 nmol/L) and the M1250T and Y1235D mutants. Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with SAR125844 leads to potent, dose-and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844. Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss. Our data demonstrated that SAR125844 is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile, supporting its clinical development in patients with MET-amplified and MET pathway-addicted tumors.

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“…http Coexistent genetic alterations in cancer-driving genes, i.e. KRAS mutations, MET amplification, PTEN loss and BIM polymorphism, etc., were indicated to be associated with primary resistance for EGFR-TKIs treatment [11][12][13][14][15]. EGFR T790M mutation, MET amplification and PIK3CA mutation, etc., were reported to be responsible for secondary resistance, of which the patients are EGFR-TKIs sensitive initially but require drug resistance after a few months [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Concurrence of EGFR amplification and sensitizing mutations indicate a better survival benefit from EGFR-TKI therapy in lung adenocarcinoma patients

et al. 2015

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Co-existence of positive MET FISH status with EGFR mutations signifies poor prognosis in lung adenocarcinoma patients

Cited by 58 publications

References 41 publications

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

The Selective Intravenous Inhibitor of the MET Tyrosine Kinase SAR125844 Inhibits Tumor Growth inMET-Amplified Cancer

Concurrence of EGFR amplification and sensitizing mutations indicate a better survival benefit from EGFR-TKI therapy in lung adenocarcinoma patients

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