Major partial response to crizotinib, a dual MET/ALK inhibitor, in a squamous cell lung (SCC) carcinoma patient with de novo c-MET amplification in the absence of ALK rearrangement

Schwab, Richárd; Peták, István; Kollar, Mihaly; Pintér, Ferenc; Várkondi, Edit; Kohánka, Andrea; Barti-Juhasz, Helga; Schönléber, Júlia; Brauswetter, Diána; Kopper, László; Urbán, László

doi:10.1016/j.lungcan.2013.10.006

Cited by 57 publications

(33 citation statements)

References 15 publications

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“…As yet, there is no clinically validated method for defining cMET amplification, and thus the actual rate of amplification in tumour samples varies significantly between studies. The correlation between sensitivity to cMET-inhibitory agents and cMET amplification remains unclear, with various studies reporting correlation [48][49][50][51], transient sensitivity [52], or no correlation [53][54][55], and as such it will be important to define a method by which copy number can be accurately determined and clinically validated. In high grade serous ovarian cancer, the TCGA cBioPortal [56,57] reveals mutations in the Met gene to be present in 1.3% of cases, and amplifications in 1.6%.…”

Section: Mis-regulation Mechanisms Of Hgf/cmetmentioning

confidence: 99%

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

Moran-Jones

2016

Mol Diagn Ther

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Survival rates for ovarian cancer have remained relatively stable for the past two decades, despite advances in surgical techniques and cytotoxic chemotherapeutics, indicating a requirement for better therapies. One pathway currently proposed for targeting is the HGF/cMET pathway. Up-regulated in a number of tumour types, cMET is a tyrosine kinase receptor expressed on epithelial cells. In ovarian cancer, it has been identified as highly expressed in the four major subtypes, with expression estimates ranging from 11-68% of cases. HGF, the only known ligand for cMET, is found at high levels in both serum and ascites in women with ovarian cancer, and proposed to induce both migration and metastasis. However, clinically validated biomarkers are not yet available for either HGF or cMET, preventing a clear understanding of the true rate of over-expression, or its correlation with prognosis.

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Section: Mis-regulation Mechanisms Of Hgf/cmetmentioning

confidence: 99%

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

Moran-Jones

2016

Mol Diagn Ther

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“…NSCLC patients with de novo MET DNA amplification are responsive to crizotinib, suggesting that MET amplification is a primary oncogenic driver and a valid clinical target (5,6). MET mutations affecting exon 14 splicing elements occur in up to 5% of lung adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non–Small Cell Lung Carcinoma with Poor Prognosis

Tong

Yeung

Chan

et al. 2016

Clinical Cancer Research

375

358

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Purpose: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-na€ ve non-small cell lung carcinoma (NSCLC).Experimental Design: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METD14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively.Results: METD14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. METD14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). METD14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio !5) was mutually exclusive to the major driver genes except METD14. Oncogenic METD14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METD14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METD14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis.Conclusions: The high incidence of METD14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients.

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“…Furthermore, crizotinib also induced a partial response in one patient with glioblastoma [95] and opne patient with squamous cell lung cancer [96], with both tumors being found to be positive for MET amplification (MET/CEP7 ratio greater than 2.2) as determined by FISH. Accumulating clinical evidence thus suggests that MET amplification as strictly defined by a MET/CEP7 ratio greater than 2.2 has the potential to act as an oncogenic driver and thereby to render at least a subset of affected tumors responsive to crizotinib [87].…”

Section: Future Challenges In Met Tki Therapy For Advanced Gastric Camentioning

confidence: 98%

MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy

Kawakami

Okamoto

2015

Gastric Cancer

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The MET protooncogene encodes the receptor tyrosine kinase c-MET (MET). Aberrant activation of MET signaling occurs in a subset of advanced malignancies, including gastric cancer, and promotes tumor cell growth, survival, migration, and invasion as well as tumor angiogenesis, suggesting its potential importance as a therapeutic target. MET can be activated by two distinct pathways that are dependent on or independent of its ligand, hepatocyte growth factor (HGF), with the latter pathway having been attributed mostly to MET amplification in gastric cancer. Preclinical evidence has suggested that interruption of the HGF-MET axis either with antibodies to HGF or with MET tyrosine kinase inhibitors (TKIs) has antitumor effects in gastric cancer cells. Overexpression of MET occurs frequently in gastric cancer and has been proposed as a potential predictive biomarker for anti-MET therapy. However, several factors can trigger such MET upregulation in a manner independent of HGF, suggesting that gastric tumors with MET overexpression are not necessarily MET driven. On the other hand, gastric cancer cells with MET amplification are dependent on MET signaling for their survival and are thus vulnerable to MET TKI treatment. Given the low prevalence of MET amplification in gastric cancer (approximately 8 %), testing for this genetic change would substantially narrow the target population but it might constitute a better biomarker than MET overexpression for MET TKI therapy. We compare aberrant MET signaling dependent on the HGF-MET axis or on MET amplification as well as address clinical issues and challenges associated with the identification of appropriate biomarkers for MET-driven tumors.

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Major partial response to crizotinib, a dual MET/ALK inhibitor, in a squamous cell lung (SCC) carcinoma patient with de novo c-MET amplification in the absence of ALK rearrangement

Cited by 57 publications

References 15 publications

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non–Small Cell Lung Carcinoma with Poor Prognosis

MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy

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