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Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with a poor prognosis that requires novel therapeutic agents. Proteome information is useful for identifying new therapeutic candidates because it directly reflects the biological phenotype. Additionally, in vitro drug screening is an effective tool to identify candidate drugs for common cancers. Hence, we attempted to identify novel therapeutic candidates for MPNST by integrating proteomic analysis and drug screening. We performed comprehensive proteomic analysis on 23 MPNST tumor samples using liquid chromatography – tandem mass spectrometry to identify therapeutic targets. We also conducted drug screening of six MPNST cell lines using 214 drugs. Proteomic analysis revealed that the MET and IGF pathways were significantly enriched in the local recurrence/distant metastasis group of MPNST, whereas drug screening revealed that 24 drugs showed remarkable antitumor effects on the MPNST cell lines. By integrating the results of these two approaches, MET inhibitors, crizotinib and foretinib, were identified as novel therapeutic candidates for the treatment of MPNST. We successfully identified novel therapeutic candidates for the treatment of MPNST, namely crizotinib and foretinib, which target the MET pathway. We hope that these candidate drugs will contribute to the treatment of MPNST. [ABSTRACT FROM AUTHOR]

• The GSH oxidase-like activity of MIL-53 depletes GSH, overcoming ferroptosis resistance in tumors. • The catalase-like activity of MIL-53 boosts photodynamic therapy by generating oxygen through the decomposition of H 2 O 2. • The photodynamic effect of MMSC generates singlet oxygen, further amplifying ferroptosis. • cMBP peptide modification attenuates MET pathway in MET-overexpressing tumors, reducing antioxidant capacity and promoting ferroptosis. • Transcriptomic analysis revealed that MMSC modulates the expression of ferroptosis-related and MET signaling pathways-related genes. Ferroptosis, a relatively recently discovered form of programmed cell death, has garnered considerable attention in the field of cancer drug discovery. However, effectively inducing ferroptosis at tumor sites and maximizing its therapeutic efficacy remains a formidable challenge. In the present study, we constructed the MIL-53@cMBP@ST/Ce6 (MMSC) nanocomplex to enhance the therapeutic efficacy of a ferroptosis-inducing drug. This was accomplished by modifying the cMBP peptide and encapsulating a small molecular ferroptosis inducer, sorafenib tosylate (ST), along with a photosensitizer, Chlorin e6 (Ce6), within the iron-based nanozyme MIL-53, which exhibits multiple enzyme-like activities. The glutathione (GSH) oxidase-like activity of MIL-53 depletes GSH, which is known to contribute to ferroptosis resistance in tumors. The catalase-like activity of MIL-53 catalyzes the decomposition of H 2 O 2 within the tumor, yielding oxygen to enhance the effect of photodynamic therapy. Concurrently, the photodynamic effect of MMSC generates singlet oxygen (1O 2), further amplifying ferroptosis. Additionally, modification of the cMBP peptide enabled MMSC to attenuate the MET pathway in MET-overexpressing tumors, thereby decreasing the antioxidant capacity of these cells to promote ferroptosis. Notably, transcriptomic analysis revealed that PDT enhances the ferroptosis pathway and modulates the expression of ferroptosis-related genes and MET signaling pathways-related genes, while Western Blot results confirmed the inhibition of GPX4 protein, a critical regulator of ferroptosis. In vivo, MMSC demonstrated a tumor-specific accumulation effect, as evidenced by fluorescence imaging, and significantly inhibited tumor growth by alleviating the hypoxic tumor microenvironment and enhancing ferroptosis at the tumor site. This study presents a novel strategy for the mechanistic investigation of augmented ferroptosis in tumor therapy. [ABSTRACT FROM AUTHOR]

The c-MET proto-oncogene (MET) plays an important role in lung oncogenesis, affecting cancer-cell survival, growth and invasiveness. The MET receptor in non-small–cell lung cancer (NSCLC) is a potential therapeutic target. The development of high-output next-generation sequencing techniques has enabled better identification of anomalies in the MET pathway, like the MET exon-14 (METex14) mutation. Moreover, analyses of epidermal growth factor-receptor (EGFR) and mechanisms of resistance to tyrosine-kinase inhibitors (TKIs) demonstrated the importance of MET amplification as an escape mechanism in patients with TKI-treated EGFR-mutated NSCLCs. This review summarizes the laboratory findings on MET and its anomalies, trial results on METex14 alterations and MET amplification in non-EGFR mutated NSCLCs, and acquired resistance to TKI in EGFR-mutated NSCLCs. The outcomes of the first trials with anti-MET agents on non-selected NSCLC patients or those selected for MET overexpression were disappointing. Two situations seem the most promising today for the use of anti-MET agents to treat these patients: tumors harboring METex14 and those EGFR-sensitive mutation mutated under TKI-EGFR with a MET-amplification mechanism of resistance or EGFR-resistance mutation. [ABSTRACT FROM AUTHOR]

STMN1 has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. However, the detailed functions and underlying mechanisms of STMN1 are still largely unknown in hepatocellular carcinoma (HCC) development. Herein, we analyzed STMN1 expression and the related clinical significance in HCC by using well‐established Protein Atlas, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cancer databases. Analysis indicated that STMN1 was highly expressed in HCC and closely associated with vascular invasion, higher histological grade, advanced clinical grade and shorter survival time in HCC patients. Overexpressing and silencing STMN1 in HCC cell lines showed that STMN1 could regulate cell proliferation, migration, drug resistance, cancer stem cell properties in vitro as well as tumor growth in vivo. Further experiments showed that STMN1 mediated intricate crosstalk between HCC and hepatic stellate cells (HSC) by triggering the hepatocyte growth factor (HGF)/MET signal pathway. When HSC were cocultured with HCC cells, HSC secreted more HGF to stimulate the expression of STMN1 in HCC cells. Mutually, STMN1 upregulation in HCC cells facilitated HSC activation to acquire cancer‐associated fibroblast (CAF) features. The MET inhibitor crizotinib significantly blocked this crosstalk and slowed tumor growth in vivo. In conclusion, our findings shed new insight on STMN1 function, and suggest that STMN1 may be used as a potential marker to identify patients who may benefit from MET inhibitor treatment. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related deaths in United States, accounting for more than one-fourth of the deaths annually. Although comparatively rare and relatively less studied, genetic abnormalities other than epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and Kirsten rat sarcoma (KRAS) mutations account for significant proportion of the driver mutations identified thus far. The targeted agents against B-rapidly accelerated fibrosarcoma (BRAF) V600E mutation, MNNG-HOS transforming gene (MET) pathway, ROS1 rearrangement, rearranged during transfection (RET) rearrangement, and HER2 pathways offer promising therapeutic options. Recruiting patients with these rarer mutations to well-designed, large multicenter trials to further validate the use of targeted agents remains a challenge. The clinical data and ongoing trials with these agents are reviewed in this article. [ABSTRACT FROM AUTHOR]

Introduction : Renal cell carcinoma (RCC) consists of distinct clinical and biologic entities, with an urgent need for novel therapies targeting histology-specific molecular drivers of cancer growth. The MET pathway is now being targeted by multiple novel agents in clinical development. This review highlights the upcoming role of MET inhibition in the treatment of RCC. Areas covered : The HGF-MET axis is now recognized as playing a vital role in the growth of papillary histology and in driving VEGF inhibitor resistance. The heterogeneity of MET alterations influences sensitivity to MET inhibition and we need predictive biomarkers for improving patient selection. In this review, we highlight the role of the MET pathway in both clear cell and non-clear cell RCC and  provide a comprehensive review of preclinical and early clinical data on multiple drugs targeting the MET pathway. Expert opinion : MET alterations can act as primary or secondary drivers of tumor growth in RCC and represents a viable therapeutic target. Combination strategies of VEGF and MET inhibitors could lead to sustained and deep responses even in non-MET driven RCC by inhibiting pathways of VEGF resistance. Addition of checkpoint inhibitors to MET inhibition has also demonstrated promising signs of early efficacy.

Introduction: The role of the c-mesenchymal-epithelial transition factor (c-MET) signaling pathway in tumor progression and invasion has been extensively studied. C-MET inhibitors have shown anti-tumor activity in NSCLC both in preclinical and in clinical trials. However, given the molecular heterogeneity of NSCLC, it is likely that only a specific subset of NSCLC patients will benefit from c-MET inhibitors. Emerging data also suggest that MET inhibitors in combination with EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) may have a role in therapy for both EGFR-TKI resistant and EGFR-TKI naïve patients. The challenges ahead are in the identification of the molecular subtypes that benefit most., Areas Covered: This review summarizes the current understanding of c-MET biology in relation to studies evaluating c-MET inhibitors in the treatment of NSCLC., Expert Opinion: MET inhibitors have the potential to benefit subsets of NSCLC patients with specific genetic alterations. Exon-14 skipping mutations appear so far to be the most promising molecular subset that is sensitive to MET inhibitors, whereas overexpression, amplification and point mutations of MET seem more challenging subgroups to target. Combination with other target agents, such as EGFR inhibitors, may represent a promising therapeutic strategy in specific areas (e.g. EGFR-TKI resistance).

Papillary renal cell carcinoma (pRCC) represents the second most common histologic variant of kidney cancer. It exhibits a different molecular signature than clear-cell carcinoma and is typically not associated with mutations in the VHL (von Hippel-Lindau) tumor suppressor gene. pRCC is less responsive to modern drugs introduced in the management of kidney cancer in the past decade. In this article, the heredity and biology of 2 main variants of pRCC are outlined. New targets that are being explored in the treatment of this disease are discussed, with particular emphasis on inhibition of mesenchymal epithelial transition (MET) and epidermal growth factor receptor (EGFR) pathways. We discuss preclinical data providing rationale for the combination of MET and EGFR inhibitors and review recently completed and ongoing clinical trials that attempt to expand our therapeutic options for this important subset of kidney cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)