An ‘in‐cell trial’ to assess the efficacy of a monovalent anti‐MET antibody as monotherapy and in association with standard cytotoxics

Benvenuti, Silvia; Gentile, Alessandra; Lazzari, Luca; Arnesano, Addolorata; Trusolino, Livio; Comoglio, Paolo M.

doi:10.1016/j.molonc.2013.12.006

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…Only patients with MET gene alterations may have an objective response (tumor regression) after receiving MET-targeted therapy, whereas targeting the HGF/MET axis in MET wild-type patients has little effect on cancer cell growth or on the efficacy of chemotherapy agents. 93 In many cases, MET inhibitors have been reported to be effective in patients with NSCLC, who have high levels of MET amplification 63,64 or METex14 skipping mutations. 38,42,51,54,[94][95][96] There are a variety of MET inhibitors, including small molecule TKIs and monoclonal antibodies (mAbs) against MET or its ligand HGF, for clinical studies of NSCLC.…”

Section: Therapeutics To Inhibit the Hgf/c-met Axismentioning

confidence: 99%

<p>MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis</p>

Liang¹,

Wang²

2020

OTT

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and has a poor prognosis. Current treatments for advanced NSCLC included traditional chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The efficacy of targeted therapy relies on oncogene addiction. Mesenchymal-epithelial transition factor (MET) gene can encode unconventional receptor tyrosine kinases with pleiotropic functions, when signals are abnormally activated, it can initiate and maintain tumor transformation, promote cell proliferation, survival, tumor invasion and angiogenesis. Thus, it is a promising therapeutic target. Previous studies have shown that elevated levels of HGF and/or overexpression of c-Met are associated with poor prognosis in lung cancer. In preclinical and clinical trials, c-MET inhibitors have shown some antitumor activity in NSCLC. Although the efficacy results of MET inhibitors in Phase III clinical trials are disappointing, given the molecular heterogeneity of NSCLC, only subgroups of patients with MET gene alterations may benefit from c-MET inhibitors. The challenge for the future is to screen out the potential beneficiaries. To solve this problem, there is need for large data analysis for the detection methods and treatment effects, to establish standards that meet the MET activation status, and determine reliable thresholds to achieve effective patient stratification and clinical decision making. This article summarized the structure of the hepatocyte growth factor (HGF)/c-Met axis, the different mechanisms of MET addiction, as well as MET amplification as acquired resistance mechanism to epidermal growth factor receptor-tyrosine kinase inhibitors, the latest advances of MET inhibitors, and immuotherapy in the treatment of NSCLC with MET alterations.

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Section: Therapeutics To Inhibit the Hgf/c-met Axismentioning

confidence: 99%

<p>MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis</p>

Liang¹,

Wang²

2020

OTT

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“…Whether there is a molecular subtype of HNSCC, and more specifically OSCC, driven by MET mutation and/or amplification that confers a susceptibility to targeted agents, needs to be further examined in sufficiently large and welldescribed patient cohorts [7]. In contrast, limited to no effects of MET-targeted therapies were observed on cell growth in wild-type MET tumor models [56]. Nevertheless, pharmacological inhibition of wild-type MET has negative effects on cell survival from apoptotic insults, migration, and metastasis [57].…”

Section: Discussionmentioning

confidence: 99%

The Occurrence of MET Ectodomain Shedding in Oral Cancer and Its Potential Impact on the Use of Targeted Therapies

Herdt

Steen

Jong

et al. 2022

Cancers

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The receptor tyrosine kinase MET has gained attention as a therapeutic target. Although MET immunoreactivity is associated with progressive disease, use of targeted therapies has not yet led to major survival benefits. A possible explanation is the lack of companion diagnostics (CDx) that account for proteolytic processing. During presenilin-regulated intramembrane proteolysis, MET’s ectodomain is shed into the extracellular space, which is followed by γ-secretase-mediated cleavage of the residual membranous C-terminal fragment. The resulting intracellular fragment is degraded by the proteasome, leading to downregulation of MET signaling. Conversely, a membrane-bound MET fragment lacking the ectodomain (MET-EC-) can confer malignant potential. Use of C- and N-terminal MET monoclonal antibodies (moAbs) has illustrated that MET-EC- occurs in transmembranous C-terminal MET-positive oral squamous cell carcinoma (OSCC). Here, we propose that ectodomain shedding, resulting from G-protein-coupled receptor transactivation of epidermal growth factor receptor signaling, and/or overexpression of ADAM10/17 and/or MET, stabilizes and possibly activates MET-EC- in OSCC. As MET-EC- is associated with poor prognosis in OSCC, it potentially has impact on the use of targeted therapies. Therefore, MET-EC- should be incorporated in the design of CDx to improve patient stratification and ultimately prolong survival. Hence, MET-EC- requires further investigation seen its oncogenic and predictive properties.

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“…Unlike chromosome 7 trisomy, which is not a primary cancer driver, MET amplification acts as a driver and represents a true biological selection [ 3 ]. In vitro and preclinical studies suggest that a ‘threshold’ of five copies of the MET gene drives addiction, thus justifying targeted therapies [ 63 ]. Although no clinical consensus exists for such a cut-off, it is critical for effective patient stratification in MET-targeted therapies.…”

Section: Met Amplificationmentioning

confidence: 99%

“…For tumors expressing wt MET (the vast majority of patients), a priori ineligible for MET-targeted therapies, it should be noted that hampering the MET signaling reduces migration and metastatic dissemination drastically without affecting the growth of cancer cells [ 63 , 177 , 178 ]. Using MET-targeted therapy might constitute a promising adjuvant therapy after tumor resection with curative intent, an ideal setting to eradicate the persistence and dissemination of subclinical tumor foci.…”

Section: Patient Stratification: a Key For Success In Targeted Therapiesmentioning

confidence: 99%

An Observatory for the MET Oncogene: A Guide for Targeted Therapies

Altintas,

Comoglio

2023

Cancers

Self Cite

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The MET proto-oncogene encodes a pivotal tyrosine kinase receptor, binding the hepatocyte growth factor (HGF, also known as scatter factor, SF) and governing essential biological processes such as organogenesis, tissue repair, and angiogenesis. The pleiotropic physiological functions of MET explain its diverse role in cancer progression in a broad range of tumors; genetic/epigenetic alterations of MET drive tumor cell dissemination, metastasis, and acquired resistance to conventional and targeted therapies. Therefore, targeting MET emerged as a promising strategy, and many efforts were devoted to identifying the optimal way of hampering MET signaling. Despite encouraging results, however, the complexity of MET’s functions in oncogenesis yields intriguing observations, fostering a humbler stance on our comprehension. This review explores recent discoveries concerning MET alterations in cancer, elucidating their biological repercussions, discussing therapeutic avenues, and outlining future directions. By contextualizing the research question and articulating the study’s purpose, this work navigates MET biology’s intricacies in cancer, offering a comprehensive perspective.

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An ‘in‐cell trial’ to assess the efficacy of a monovalent anti‐MET antibody as monotherapy and in association with standard cytotoxics

Cited by 10 publications

References 31 publications

<p>MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis</p>

<p>MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis</p>

The Occurrence of MET Ectodomain Shedding in Oral Cancer and Its Potential Impact on the Use of Targeted Therapies

An Observatory for the MET Oncogene: A Guide for Targeted Therapies

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