Transforming properties of <scp>MET</scp> receptor exon 14 skipping can be recapitulated by loss of the <scp>CBL</scp> ubiquitin ligase binding site

Fernandes, Marie; Paget, Sonia; Kherrouche, Zoulika; Truong, Marie‐José; Vinchent, Audrey; Meneboo, Jean-Pascal; Werkmeister, Elisabeth; Descarpentries, Clotilde; Figeac, Martin; Cortot, A.; Tulasne, David

doi:10.1002/1873-3468.14702

Cited by 6 publications

(1 citation statement)

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“…Only a few functional studies have explored the respective roles of the three known regulatory sites of the juxtamembrane domain in regulating receptor and downstream signalling pathway activation. It seems, however, that the CBL binding site, involved in MET ubiquitination, is a crucial regulatory site ( Fernandes et al, 2023b ; Miao and Xu, 2019 ). Furthermore, when METex14Del is present, other known oncogenic drivers such as KRAS (Kirsten rat sarcoma viral oncogene homolog), EGFR (epidermal growth factor receptor), and HER2 (human epidermal growth factor receptor 2) tend to be absent, which suggests that METex14Del can promote oncogenesis in the absence of other oncogenic drivers ( Pilotto et al, 2017 ).…”

Section: Met Mutations Leading To Exon 14 Skippingmentioning

confidence: 99%

Recording and classifying MET receptor mutations in cancers

Guérin,

Tulasne

2024

eLife

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Tyrosine kinase inhibitors (TKI) directed against MET have been recently approved to treat advanced non-small cell lung cancer (NSCLC) harbouring activating MET mutations. This success is the consequence of a long characterization of MET mutations in cancers, which we propose to outline in this review. MET, a receptor tyrosine kinase (RTK), displays in a broad panel of cancers many deregulations liable to promote tumour progression. The first MET mutation was discovered in 1997, in hereditary papillary renal cancer (HPRC), providing the first direct link between MET mutations and cancer development. As in other RTKs, these mutations are located in the kinase domain, leading in most cases to ligand-independent MET activation. In 2014, novel MET mutations were identified in several advanced cancers, including lung cancers. These mutations alter splice sites of exon 14, causing in-frame exon 14 skipping and deletion of a regulatory domain. Because these mutations are not located in the kinase domain, they are original and their mode of action has yet to be fully elucidated. Less than five years after the discovery of such mutations, the efficacy of a MET TKI was evidenced in NSCLC patients displaying MET exon 14 skipping. Yet its use led to a resistance mechanism involving acquisition of novel and already characterized MET mutations. Furthermore, novel somatic MET mutations are constantly being discovered. The challenge is no longer to identify them but to characterize them in order to predict their transforming activity and their sensitivity or resistance to MET TKIs, in order to adapt treatment.

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Section: Met Mutations Leading To Exon 14 Skippingmentioning

confidence: 99%

Recording and classifying MET receptor mutations in cancers

Guérin,

Tulasne

2024

eLife

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Insights into the role of derailed endocytic trafficking pathway in cancer: From the perspective of cancer hallmarks

Guo,

Zhou,

Zheng

et al. 2024

Pharmacological Research

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Transcriptional program-based deciphering of the MET exon 14 skipping regulation network

Truong,

Pawlak,

Meneboo

et al. 2024

Preprint

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The MET exon 14 skipping mutation (named METex14del) described in lung cancer leads to prolonged activation of signaling pathways and aberrant cell responses, but the link between HGF signaling and cell responses remains unclear. A putative regulatory network of influential regulators of target genes was constructed from the transcriptomes of lung cancer cell lines. Overlaying this reference network with transcriptomic data from METex14del-expressing cells, stimulated or not by HGF, revealed a major regulatory node consisting mainly of the transcription factors ETS1, FOSL1 and SMAD3. HGF activation of METex14del induced the phosphorylation of these master regulators and the expression of their predicted target genes in a RAS-ERK pathway-dependent manner. Furthermore, most of the transcription factors in the regulatory node are known regulators of epithelial-mesenchymal transition, consistent with their involvement in migration and invasion. New modeling with transcriptomic data from MEK inhibitor-treated METex14del cells validated the key role of RAS-ERK pathway regulators and their target genes in METex14del receptor activation. Thus, we report an original strategy to identify key transcriptional nodes associated with specific signaling pathways that may become novel therapeutic targets.

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Transforming properties of MET receptor exon 14 skipping can be recapitulated by loss of the CBL ubiquitin ligase binding site

Cited by 6 publications

References 50 publications

Recording and classifying MET receptor mutations in cancers

Recording and classifying MET receptor mutations in cancers

Insights into the role of derailed endocytic trafficking pathway in cancer: From the perspective of cancer hallmarks

Transcriptional program-based deciphering of the MET exon 14 skipping regulation network

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