MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure

Boccaccio, Carla; Comoglio, Paolo M.

doi:10.1016/j.ceb.2014.09.008

Cited by 38 publications

(31 citation statements)

References 75 publications

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“…The MET gene, located on chromosome 7q31, encodes for the TK receptor for ‘Scatter Factor’ or Hepatocyte Growth Factor (HGF), which detects adverse micro-environmental conditions and drives cell invasion and metastasis through the transcriptional activation of the invasive growth signature , a genetic program also defined as the epithelial-mesenchymal transition (EMT) [8]. The latter includes cell–cell dissociation and scattering, migration, cellular proliferation, resistance to anoikis and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…MET-driven invasive growth is aberrantly activated in cancer, mainly as a late event, leading to distant dissemination and malignant progression. More recent studies have reported that MET amplified cancer clones are selected under therapeutic pressure in a context of molecularly heterogeneous lesions exposed to targeted therapies or radiotherapy [8, 122–125]. In CSC, both the occurrence of genetic lesions (as amplification) and physiological expression of MET can contribute to tumorigenesis and therapeutic resistance, by sustaining the invasive growth phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Ockham’s razor for the MET-driven invasive growth linking idiopathic pulmonary fibrosis and cancer

et al. 2016

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Background: Idiopathic pulmonary fibrosis (IPF) identifies a specific lung disorder characterized by chronic, progressive fibrosing interstitial pneumonia of unknown etiology, which lacks effective treatment. According to the current pathogenic perspective, the aberrant proliferative events in IPF resemble those occurring during malignant transformation. Main body:Receptor tyrosine kinases (RTK) are known to be key players in cancer onset and progression. It has been demonstrated that RTK expression is sometimes also altered and even druggable in IPF. One example of an RTK-the MET proto-oncogene-is a key regulator of invasive growth. This physiological genetic program supports embryonic development and post-natal organ regeneration, as well as cooperating in the evolution of cancer metastasis when aberrantly activated. Growing evidence sustains that MET activation may collaborate in maintaining tissue plasticity and the regenerative potential that characterizes IPF. Conclusion:The present work aims to elucidate-by applying the logic of simplicity-the bio-molecular mechanisms involved in MET activation in IPF. This clarification is crucial to accurately design MET blockade strategies within a fully personalized approach to IPF.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ockham’s razor for the MET-driven invasive growth linking idiopathic pulmonary fibrosis and cancer

et al. 2016

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“…Clusters of PDX with upregulation in the EGFR/HER2/HER3 family of RTKs, c-Kit upregulation, as well as MET were identified. We selected the proto oncogene MET (32, 33) as another promising target for second line therapies. The 25% (3/12) incidence of MET amplifications in this set of BRAF inhibitor progressed PDX was significantly higher than in the melanoma cancer genome atlas (TCGA) at 8/129 BRAF hotspot mutated, 0/17 BRAF non hotspot, and 3/149 BRAF wild type yielding a total of 11/299 or 3.7%.…”

Section: Resultsmentioning

confidence: 99%

Personalized Preclinical Trials in BRAF Inhibitor–Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies

Krepler

Xiao

Sproesser

et al. 2016

Clinical Cancer Research

111

119

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Purpose To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models. Methods We established 12 PDX from BRAF inhibitor progressed melanoma patients. Following expansion, PDX were analyzed using targeted sequencing and reverse phase protein arrays (RPPA). By using multi-arm pre-clinical trial designs, we identified efficacious precision medicine approaches. Results We identified alterations previously described as drivers of resistance: NRAS mutations in 3 PDX, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7. At the protein level, re-activation of phospho MAPK predominated, with parallel activation of PI3K in a subset. Second line efficacy of the pan-PI3K inhibitor BKM120 with either BRAF (encorafenib) /MEK (binimetinib) inhibitor combination or the ERK inhibitor VX-11e was confirmed in vivo. Amplification of MET was observed in 3 PDX models, a higher frequency than expected and a possible novel mechanism of resistance. Importantly, MET amplification alone did not predict sensitivity to the MET inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy and high pMET. The triple combination capmatinib/encorafenib/binimetinib resulted incomplete and sustained tumor regression in all animals. Conclusions Genomic and proteomic data integration identifies dual core pathway inhibition as well as MET as combinatorial targets. These studies provide evidence for biomarker development to appropriately select patients' personalized therapies and avoid treatment failures.

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“…Activation of c-Met drives a complex genetic program termed invasive growth, which is pivotal in driving cancer cell invasion and metastasis (18,39). In vitro, (Fig.…”

Section: Scc244 Inhibited C-met-dependent Neoplastic Phenotypes Of Mementioning

confidence: 99%

Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models

Chen

Xia

et al. 2018

Molecular Cancer Therapeutics

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Because the receptor tyrosine kinase c-Met plays a critical role in tumor growth, metastasis, tumor angiogenesis and drug resistance, the c-Met axis represents an attractive therapeutic target. Herein, we report the first preclinical characterization of SCC244, a novel, potent and highly selective inhibitor of c-Met kinase. SCC244 showed subnanomolar potency against c-Met kinase activity and high selectivity versus 312 other tested protein kinases, making it one of the most selective c-Met inhibitors described to date.

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MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure

Cited by 38 publications

References 75 publications

Ockham’s razor for the MET-driven invasive growth linking idiopathic pulmonary fibrosis and cancer

Ockham’s razor for the MET-driven invasive growth linking idiopathic pulmonary fibrosis and cancer

Personalized Preclinical Trials in BRAF Inhibitor–Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies

Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models

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