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Papillary renal-cell carcinomas account for 15 to 20% of kidney cancers. Type 1, which is often multifocal and more indolent, was associated with mutations in MET . Type 2, which is more heterogeneous and aggressive, was associated with activation of the NRF2-ARE pathway. Kidney cancer, or renal-cell carcinoma, is not a single disease but is made up of various types of cancer that are characterized by different genetic drivers; each type has distinct histologic features and a distinct clinical course and response to therapy. 1 , 2 Papillary renal-cell carcinoma, which accounts for 15 to 20% of kidney cancers, is a heterogeneous disease with histologic subtypes and variations in both disease progression and patient outcomes. Papillary renal-cell carcinoma has two main subtypes: type 1, which is often multifocal, is characterized by papillae and tubular structures covered with small cells containing basophilic cytoplasm and small, uniform, . . .

Key Points Hepatocyte growth factor (HGF) and its tyrosine kinase receptor MET (also known as HGF receptor) mediate invasive growth, a complex programme in which cells lose contacts with their neighbours, mobilize towards adjacent surroundings, resist apoptotic insults and proliferate. During development, HGF and MET are essential for the growth and survival of epithelial cell types and for the migration of muscle progenitors. In adult physiology, MET exerts a trophic activity that attenuates tissue damage and promotes the regeneration of several organs. In tumours, MET stimulates the motility and survival of cancer cells as well as angiogenesis, thereby acting as a powerful expedient for neoplastic invasion and production of secondary metastases. MET gain-of-function genetic lesions can also be selected to maintain the transformed phenotype of some primary tumours, which seem to be 'addicted' to continued MET activity for their relentless growth. MET signals are channelled by an unconventional multifunctional docking site consisting of two tyrosines that, when phosphorylated, recruit a wide spectrum of transducers. Interaction with the GRB2-associated-binding protein 1 (GAB1) multi-adaptor protein is critical for transduction of most MET signalling pathways, whereas tissue-specific interactions with other surface partners such as the α6β4 integrin and the CD44 adhesion molecule regulate quantitative modulation of downstream signalling and cytoskeletal compartmentalization, respectively. MET signals emanate not only from the plasma membrane but also from endosomal compartments, and MET internalization seems to be required for efficient activation and proper subcellular localization of distal transducers such as extracellular signal-regulated kinases (ERKs) and signal transducer and activator of transcription 3 (STAT3). MET also undergoes other trafficking events — including extracellular shedding, intracellular cleavage, ubiquitylation, degradation and membrane recycling — which regulate the strength of MET activation and the ensuing robustness of MET-dependent signals. In distinct cells and tissues, specific activities that are controlled by MET seem to be fulfilled by dedicated signalling cascades, with some transducers dominating over others according to context, timing and biological complexity. This suggests that the specificity of MET-dependent responses is determined, at least in part, by qualitative differences in signalling outputs. The MET receptor promotes tissue remodelling by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation, which can be exploited in regenerative medicine and cancer therapy. The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.

The use of ATP competitive kinase inhibitors against the pseudokinase Her3 has been largely unsuccessful. Hydrophobic tagging of a covalent kinase inhibitor promotes Her3 degradation and prevents productive dimerization and signaling. Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ∼60 other pseudokinases found in human cells.

Mutations in the kinase and juxtamembrane domains of the MET Receptor Tyrosine Kinase are responsible for oncogenesis in various cancers and can drive resistance to MET-directed treatments. Determining the most effective inhibitor for each mutational profile is a major challenge for MET-driven cancer treatment in precision medicine. Here, we used a deep mutational scan (DMS) of ~5764 MET kinase domain variants to profile the growth of each mutation against a panel of 11 inhibitors that are reported to target the MET kinase domain. We validate previously identified resistance mutations, pinpoint common resistance sites across type I, type II, and type I ½ inhibitors, unveil unique resistance and sensitizing mutations for each inhibitor, and verify non-cross-resistant sensitivities for type I and type II inhibitor pairs. We augment a protein language model with biophysical and chemical features to improve the predictive performance for inhibitor-treated datasets. Together, our study demonstrates a pooled experimental pipeline for identifying resistance mutations, provides a reference dictionary for mutations that are sensitized to specific therapies, and offers insights for future drug development.

The emergence of targeted therapies for MET exon 14 (METex14) skipping mutations has significantly changed the treatment landscape for NSCLC and other solid tumors. The skipping of METex14 results in activating the MET-HGF pathway and promoting tumor cell proliferation, migration, and preventing apoptosis. Type Ib MET inhibitors, designed to selectively target the “DFG-in” conformation of MET, characteristically bind to the ATP-binding pocket of MET in a U-shaped conformation, extending into the solvent-accessible region and interact strongly with residue Y1230 through π-π interactions, have shown remarkable efficacy in treating METex14-altered NSCLC, including cases with brain metastases (BMs). Notably, vebreltinib and capmatinib have demonstrated superior blood-brain barrier (BBB) permeability in both computational and experimental models, highlighting their potential for treating the central nervous system (CNS) metastases. P-glycoprotein (P-gp) is highly expressed in the BBB, which limits the brain uptake of many highly lipophilic drugs. Despite challenges posed by P-gp mediated efflux, vebreltinib has emerged as a promising candidate for CNS treatment due to its favorable pharmacokinetic profile and minimal susceptibility to P-gp efflux. This study underscores the importance of molecular dynamics simulations in predicting drug efficacy and BBB penetration, providing valuable insights for the development of CNS-targeted metastases therapies.

Somasekar Seshagiri, James Brugarolas and colleagues report the mutational landscape of 167 non–clear cell renal cell carcinomas (nccRCCs) from multiple subtypes. They identify subtype-specific driver mutations and gene fusions, including ones involving MITF , which result in expression of the anti-apoptotic protein BIRC7 and might thus indicate candidates for treatment with BIRC7 inhibitors. To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non–clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET , NF2 , SLC5A3 , PNKD and CPQ . MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53 , PTEN , FAAH2 , PDHB , PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1 - MITF fusion. Ectopic expression of the ACTG1 - MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.

Binding of hepatocyte growth factor (HGF) to the receptor tyrosine kinase MET is implicated in the malignant process of multiple cancers, making disruption of this interaction a promising therapeutic strategy. However, targeting MET with bivalent antibodies can mimic HGF agonism via receptor dimerization. To address this limitation, we have developed onartuzumab, an Escherichia coli -derived, humanized, and affinity-matured monovalent monoclonal antibody against MET, generated using the knob-into-hole technology that enables the antibody to engage the receptor in a one-to-one fashion. Onartuzumab potently inhibits HGF binding and receptor phosphorylation and signaling and has antibody-like pharmacokinetics and antitumor activity. Biochemical data and a crystal structure of a ternary complex of onartuzumab antigen-binding fragment bound to a MET extracellular domain fragment, consisting of the MET Sema domain fused to the adjacent Plexins, Semaphorins, Integrins domain (MET Sema-PSI), and the HGF β-chain demonstrate that onartuzumab acts specifically by blocking HGF α-chain (but not β-chain) binding to MET. These data suggest a likely binding site of the HGF α-chain on MET, which when dimerized leads to MET signaling. Onartuzumab, therefore, represents the founding member of a class of therapeutic monovalent antibodies that overcomes limitations of antibody bivalency for targets impacted by antibody crosslinking.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths, remaining a significant challenge in terms of early detection, effective treatment, and improving patient survival rates. In this study, we investigated the anticancer mechanism of rubiarbonol B (Ru-B) and its derivative 3- O -acetylrubiarbonol B (ARu-B), a pentacyclic terpenoid in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. Concentration- and time-dependent cytotoxicity was observed for both Ru-B and ARu-B. The in vitro kinase assay showed that ARu-B treatment inhibited epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition (MET), and AKT1, and their phosphorylation in HCC827 cells. A molecular docking model suggested that ARu-B could interact with EGFR and MET in different ways, either by binding to the ATP pocket or the substrate pocket. ARu-B induced reactive oxygen species (ROS) generation and cell cycle arrest. The induction of apoptosis through caspase activation was confirmed by preventing cytotoxicity with Z-VAD-FMK pretreatment. Taken together, ARu-B inhibited the growth of both GEF-sensitive and GEF-resistant NSCLC cells by targeting EGFR, MET, and AKT and inducing ROS generation and caspase activation. Further studies on ARu-B can improve the treatment of chemotherapy-resistant NSCLC through the development of effective ARu-B-based anticancer agents.

c-Met is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor (HGF), activates downstream pathways with diverse cellular functions that are important in organ development and cancer progression. Anomalous c-Met signalling has been described in a variety of cancer types, and the receptor is regarded as a novel therapeutic target. In breast cancer there is a need to develop new treatments, particularly for the aggressive subtypes such as triple-negative and basal-like cancer, which currently lack targeted therapy. Over the last two decades, much has been learnt about the functional role of c-Met signalling in different models of breast development and cancer. This work has been complemented by clinical studies, establishing the prognostic significance of c-Met in tissue samples of breast cancer. While the clinical trials of anti-c-Met therapy in advanced breast cancer progress, there is a need to review the existing evidence so that the potential of these treatments can be better appreciated. The aim of this article is to examine the role of HGF/c-Met signalling in in vitro and in vivo models of breast cancer, to describe the mechanisms of aberrant c-Met signalling in human tissues, and to give a brief overview of the anti-c-Met therapies currently being evaluated in breast cancer patients. We will show that the HGF/c-Met pathway is associated with breast cancer progression and suggest that there is a firm basis for continued development of anti-c-Met treatment, particularly for patients with basal-like and triple-negative breast cancer.

Key Points The Met receptor tyrosine kinase binds to, and is activated by, its specific ligand, the growth and motility factor HGF/SF (hepatocyte growth factor/scatter factor). HGF/SF shares its overall domain structure with proteinases of the plasminogen family; the domain structure of Met is unique and its extracellular sequence is related to semaphorins and the semaphorin receptors (plexins). Met activation results in tyrosine phosphorylation of the receptor at a unique bidentate docking site in the carboxy-terminal end of Met, which recruits signalling molecules such as the scaffolding adaptor Gab1 (growth-factor-receptor-bound protein 2 (Grb2)-associated binder 1). Gab1 mediates most of the complex cellular responses to Met activation. The juxtamembrane domain of Met contains an additional docking site that, when phosphorylated, recruits Cbl, a ubiquitin ligase, which results in Met ubiquitylation, endocytosis and degradation. Met activation can induce proliferation, dissociation of epithelial cells (scattering) and motility. Furthermore, signals from Met elicit a complex morphogenic response — the formation of branched tubules from epithelial cells grown in a collagen matrix. During development, Met and HGF/SF are essential for the growth and survival of epithelial cell types and for migration of muscle progenitors. In adult physiology, Met activity prevents tissue damage and enhances liver regeneration. Met is activated in human cancer by several molecular mechanisms, for example: mutations that alter the sequence and activity of the kinase domain; by overexpression; or by simultaneous expression of receptor and ligand, which results in the autocrine stimulation of cancer cells. Met and HGF/SF are important targets for cancer therapy and many efforts are directed towards the identification of inhibitors that are active in vivo . Hepatocyte growth factor/scatter factor and its receptor, the tyrosine kinase Met, arose late in evolution and are unique to vertebrates. In spite of this, Met uses molecules such as Gab1 — homologues of which are present in Caenorhabditis elegans and Drosophila melanogaster — for downstream signalling. Pivotal roles for Met in development and cancer have been established: Met controls cell migration and growth in embryogenesis; it also controls growth, invasion and metastasis in cancer cells; and activating Met mutations predispose to human cancer.