Differential Immune Checkpoint Protein Expression in HNSCC: The Role of HGF/MET Signaling.

Although inhibitors targeting the PD1/PD-L1 immune checkpoint are showing comparably good outcomes, a significant percentage of head and neck squamous cell carcinoma (HNSCC) patients do not respond to treatment. Apart from using different treatment strategies, another possibility would be to target other immune checkpoints operating in these non-responding tumors. To obtain an overview of which checkpoint ligands are expressed on HNSCC tumor cells and if these ligands are affected by HGF/MET signaling, we used mRNA sequencing and antibody-based techniques for identifying checkpoint ligands in six HNSCC tumor cell lines. Furthermore, we compared our results to mRNA sequencing data. From the checkpoint ligands we investigated, VISTA was expressed the highest at the RNA level and was also the most ubiquitously expressed. PD-L2 and B7-H3 were expressed comparably lower and were not present in all cell lines to the same extent. B7-H4, however, was only detectable in the Detroit 562 cell line. Concerning the effect of HGF on the ligand levels, PD-L2 expression was enhanced with HGF stimulation, whereas other checkpoint ligand levels decreased with stimulation. B7-H4 levels in the Detroit 562 cell line drastically decreased with HGF stimulation. This is of interest because both the checkpoint ligand and the growth factor are reported to be connected to epithelial-mesenchymal transition in the literature.

Discovery of Potent and Selective c-Met Degraders for Hepatocellular Carcinoma Treatment.

Targeting c-Met is a clinical trend for the precise treatment of HCC, but the potential issue of acquired drug resistance cannot be ignored. Targeted protein degradation technology has demonstrated promising prospects in disease treatment and overcoming drug resistance due to its special mechanism of action. In this study, we designed and synthesized two series of novel c-Met degraders and conducted a systematic biological evaluation of the optimal compound H11. H11 exhibited good c-Met degradation activity and anti-HCC activity. Importantly, H11 also demonstrated more potent inhibitory activity against Ba/F3-TPR-MET-D1228N and Ba/F3-TPR-MET-Y1230H cell lines than did tepotinib. In summary, H11 displayed potent anti-HCC activity as a degrader and may overcome resistance to type Ib inhibitors, making it a new therapeutic strategy for HCC with MET alterations.

[Intraperitoneal injection of human-derived anti-c-Met single-chain antibody inhibits the growth of transplanted tumours in A549 lung adenocarcinoma-loaded mice].

Objective To verify the anti-tumor effect of the mesenchymal-epithelial transition single-chain antibody (Met scFv) on subcutaneously transplanted tumors in nude mice. Methods A tumor model was established in nude mice by subcutaneous injection of A549 lung adenocarcinoma cells. Once the tumors were formed, IRDye680 LT N-hydroxysuccinimide (NHS) ester-labeled Met scFv was administered intraperitoneally. Real-time monitoring was conducted using a small animal imager to observe the dynamic distribution of the antibody in tumor-bearing mice. The affinity between c-Met and the antibody in tumor cells was detected. Tumor volume changes were observed and the tumor growth curve were plotted following regular tail vein injections of Met scFv. Immunohistochemical staining was employed to determine whether Met scFv could effectively bind to the c-Met antigen in tumor tissues. Results The distribution of Met scFv in nude mice showed that it was primarily located in the peritoneal cavity within the first 3 hours. After approximately 48 hours, fluorescent signals began to accumulate in the tumor tissue. Immunohistochemical staining of the tumors revealed high expression of c-Met in the tumor tissues; regular tail vein injections of Met scFv significantly slowed down the growth of tumors in mice. Conclusion Met scFv specifically recognizes tumor cells in vivo and exhibites significant anti-tumor activity.

Reproducibility of c-Met Immunohistochemical Scoring (Clone SP44) for Non-Small Cell Lung Cancer Using Conventional Light Microscopy and Whole Slide Imaging.

Emerging therapies for non-small cell lung cancer targeting c-Met overexpression have recently demonstrated promising results. However, the evaluation of c-Met expression can be challenging. We aimed to study the inter and intraobserver reproducibility of c-Met expression evaluation. One hundred ten cases with non-small cell lung cancer (40 biopsies and 70 surgical specimens) were retrospectively selected in a single laboratory (LPCE) and evaluated for c-Met expression. Six pathologists (4 seniors and 2 juniors) evaluated the H-score and made a 3-tier classification of c-Met expression for all cases, using conventional light microscopy (CLM) and whole slide imaging (WSI). The interobserver reproducibility with CLM gave global Cohen Kappa coefficients (ƙ) ranging from 0.581 (95% CI: 0.364-0.771) to 0.763 (95% CI: 0.58-0.92) using the c-Met 3-tier classification and H-score, respectively. ƙ was higher for senior pathologists and biopsy samples. The interobserver reproducibility with WSI gave a global ƙ ranging from 0.543 (95% CI: 0.33-0.724) to 0.905 (95% CI: 0.618-1) using the c-Met H-score and 2-tier classification (≥25% 3+), respectively. ƙ for intraobserver reproducibility between CLM and WSI ranged from 0.713 to 0.898 for the c-Met H-score and from 0.600 to 0.779 for the c-Met 3-tier classification. We demonstrated a moderate to excellent interobserver agreement for c-Met expression with a substantial to excellent intraobserver agreement between CLM and WSI, thereby supporting the development of digital pathology. However, some factors (scoring method, type of tissue samples, and expertise level) affect reproducibility. Our findings highlight the importance of establishing a consensus definition and providing further training, particularly for inexperienced pathologists, for c-Met immunohistochemistry assessment in clinical practice.

The MET Family of Receptor Tyrosine Kinases Promotes a Shift to Pro-Tumor Metabolism.

The development and growth of cancer is fundamentally dependent on pro-tumor changes in metabolism. Cancer cells generally shift away from oxidative phosphorylation as the primary source of energy and rely more heavily on glycolysis. Receptor tyrosine kinases (RTKs) are a type of receptor that is implicated in this shift to pro-tumor metabolism. RTKs are important drivers of cancer growth and metastasis. One such family of RTKs is the MET family, which consists of MET and RON (MST1R). The overexpression of either MET or RON has been associated with worse cancer patient prognosis in a variety of tumor types. Both MET and RON signaling promote increased glycolysis by upregulating the expression of key glycolytic enzymes via increased MYC transcription factor activity. Additionally, both MET and RON signaling promote increased cholesterol biosynthesis downstream of glycolysis by upregulating the expression of SREBP2-induced cholesterol biosynthesis enzymes via CTTNB1. These changes in metabolism, driven by RTK activity, provide potential targets in limiting tumor growth and metastasis via pharmacological inhibition or modifications in diet. This review summarizes pro-tumor changes in metabolism driven by the MET family of RTKs. In doing so, we will offer our unique perspective on metabolic pathways that drive worse patient prognosis and provide suggestions for future study.

The Therapeutic Role of NPS-1034 in Pancreatic Ductal Adenocarcinoma as Monotherapy and in Combination with Chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in terms of diagnosis and treatment, with limited therapeutic options and a poor prognosis. This study explored the potential therapeutic role of NPS-1034, a kinase inhibitor targeting MET and AXL, in PDAC. The investigation included monotherapy with NPS-1034 and its combination with the commonly prescribed chemotherapy agents, fluorouracil and oxaliplatin. Our study revealed that NPS-1034 induces cell death and reduces the viability and clonogenicity of PDAC cells in a dose-dependent manner. Furthermore, NPS-1034 inhibits the migration of PDAC cells by suppressing MET/PI3K/AKT axis-induced epithelial-to-mesenchymal transition (EMT). The combination of NPS-1034 with fluorouracil or oxaliplatin demonstrated a synergistic effect, significantly reducing cell viability and inducing tumor cell apoptosis compared to monotherapies. Mechanistic insights provided by next-generation sequencing indicated that NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells. This suggests a broader role for NPS-1034 beyond MET and AXL inhibition, positioning it as a potential immunity modulator. Overall, these findings highlight the anticancer potential of NPS-1034 in PDAC treatment in vitro, both as a monotherapy and in combination with traditional chemotherapy, offering a promising avenue for further in vivo investigation before clinical exploration.

A genetic mouse model mimicking MET related human osteofibrous dysplasia is characterized by delays in fracture repair and defective osteogenesis.

Osteofibrous dysplasia (OFD) is a rare, benign, fibro-osseous lesion that occurs most commonly in the tibia of children. Tibial involvement leads to bowing and predisposes to the development of a fracture which exhibit significantly delayed healing processes, leading to prolonged morbidity. We previously identified gain-of-function mutations in the MET gene as a cause for OFD. In our present study, we test the hypothesis that gain-of-function MET mutations impair bone repair due to reduced osteoblast differentiation. A heterozygous Met exon 15 skipping (MetΔ15-HET) mouse was created to imitate the human OFD mutation. The mutation results in aberrant and dysregulation of MET-related signaling determined by RNA-seq in the murine osteoblasts extracted from the wide-type and genetic mice. Although no gross skeletal defects were identified in the mice, fracture repair was delayed in MetΔ15-HET mice, with decreased bone formation observed 2-week postfracture. Our data are consistent with a novel role for MET-mediated signaling regulating osteogenesis.

E2F1-Associated Purine Synthesis Pathway Is a Major Component of the MET-DNA Damage Response Network.

Various lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways in which interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with the formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acid, and lipid metabolism. 5'-Phosphoribosyl-N-formylglycinamide, a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase, which catalyzes 5'-phosphoribosyl-N-formylglycinamide synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTP depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTP reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis. SIGNIFICANCE: Maintenance of genome stability prevents disease and affiliates with growth factor receptor tyrosine kinases. We identified de novo purine synthesis as a pathway in which key enzymatic players are regulated through MET receptor and whose depletion via MET targeting explains MET inhibition-associated formation of DNA double-strand breaks. The mechanistic importance of MET inhibition-dependent E2F1 downregulation for interference with DNA integrity has translational implications for MET-targeting-based treatment of malignancies.

Spatiotemporal regulation of the hepatocyte growth factor receptor MET activity by sorting nexins 1/2 in HCT116 colorectal cancer cells.

Cumulative research findings support the idea that endocytic trafficking is crucial in regulating receptor signaling and associated diseases. Specifically, strong evidence points to the involvement of sorting nexins (SNXs), particularly SNX1 and SNX2, in the signaling and trafficking of the receptor tyrosine kinase (RTK) MET in colorectal cancer (CRC). Activation of hepatocyte growth factor (HGF) receptor MET is a key driver of CRC progression. In the present study, we utilized human HCT116 CRC cells with SNX1 and SNX2 genes knocked out to demonstrate that their absence leads to a delay in MET entering early endosomes. This delay results in increased phosphorylation of both MET and AKT upon HGF stimulation, while ERK1/2 (extracellular signal-regulated kinases 1 and 2) phosphorylation remains unaffected. Despite these changes, HGF-induced cell proliferation, scattering, and migration remain similar between the parental and the SNX1/2 knockout cells. However, in the absence of SNX1 and SNX2, these cells exhibit increased resistance to TRAIL-induced apoptosis. This research underscores the intricate relationship between intracellular trafficking, receptor signaling, and cellular responses and demonstrates for the first time that the modulation of MET trafficking by SNX1 and SNX2 is critical for receptor signaling that may exacerbate the disease.

Selective inhibition of c-Met signaling pathways with a bispecific DNA nanoconnector for the targeted therapy of cancer.

Hepatocyte growth factor receptor (c-Met) is a suitable molecular target for the targeted therapy of cancer. Novel c-Met-targeting drugs need to be developed because conventional small-molecule inhibitors and antibodies of c-Met have some limitations. To synthesize such drugs, we developed a bispecific DNA nanoconnector (STPA) to inhibit c-Met function. STPA was constructed by using DNA triangular prism as a scaffold and aptamers as binding molecules. After c-Met-specific SL1 and nucleolin-specific AS1411 aptamers were integrated with STPA, STPA could bind to c-Met and nucleolin on the cell membrane. This led to the formation of the c-Met/STPA/nucleolin complex, which in turn blocked c-Met activation. In vitro experiments showed that STPA could not only inhibit the c-Met signaling pathways but also facilitate c-Met degradation through lysosomes. STPA also inhibited c-Met-promoted cell migration, invasion, and proliferation. The results of in vivo experiments showed that STPA could specifically target to tumor site in xenograft mouse model, and inhibit tumor growth with low toxicity by downregulating c-Met pathways. This study provided a novel and simple strategy to develop c-Met-targeting drugs for the targeted therapy of cancer.

Prolonged Response to Afatinib and Crizotinib in a Rare Case of EGFR-, HER2-, MET- and ROS1-Alterated Lung Adenocarcinoma.

We present the case of a 70-year-old never-smoking female patient with epidermal growth factor receptor (EGFR) p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of first-line treatment with erlotinib, progression occurred and platinum/pemetrexed was initiated, followed by a response for more than two years. After the progression, the molecular testing of a vertebral metastasis revealed a ROS proto-oncogene 1 (ROS1) translocation and a human epidermal growth factor receptor 2 (HER2) p.S310F mutation, in addition to the known EGFR p.L858R mutation. Crizotinib then led to a durable response of 17 months. The molecular retesting of the tumour cells obtained from the recurrent pleural effusion revealed the absence of the ROS1 translocation, whereas the EGFR and HER2 mutations were still present. Afatinib was added to the crizotinib, and the combination treatment resulted in another durable response of more than two years. The patient died more than 7 years after the initial diagnosis of metastatic NSCLC. This case demonstrates that the repeated molecular testing of metastatic NSCLC may identify new druggable genomic alterations that can impact the patient management and improve the patient outcome.

Activated Gab1 drives hepatocyte proliferation and anti-apoptosis in liver fibrosis via potential involvement of the HGF/c-Met signaling axis.

Chronic liver diseases are caused by hepatic viral infection, chemicals, and metabolic stress. The protein Grb2-associated binder 1 (Gab1) binds to various growth factor receptors, and triggers cell differentiation/survival signaling pathways. To identify signaling molecules involved in the progression of liver diseases, we performed reverse-phase protein microarray (RPMA)-based screening of hepatocytes isolated from humanized mice after acute HCV infection. Acute viral infection in humanized liver mice significantly decreased the level of hepatocyte p-Gab1. Moreover, hepatoma cells upon HCV infection decreased Gab1 mRNA at later times of infection (D3 to D5) and p-Gab1 level was inversely related to the production of TGF-ß. In contrast, the level of p-Gab1 was increased in CCL4-induced fibrotic liver. Hepatoma cells showed elevation of p-Gab1, along with an increase in STAT3 and ERK activation, upon treatment with HGF (ligand of HGF receptor/c-Met) and CCL4. In Gab1 knockdown hepatoma cells, cell proliferative signaling activity was reduced but the level of activated caspase-3 was increased. These findings suggest that hepatocyte Gab1 expression may play a role in promoting liver fibrosis progression by triggering ERK activation and inhibiting apoptosis. It implies that the Gab1-mediated signaling pathway would be a promising therapeutic target to treat chronic liver diseases.

KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination.

BACKGROUND: KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. METHODS: Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. RESULTS: Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. CONCLUSIONS: We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

Synthesis and Evaluation of a Novel c-Met-Targeting Cyclic Peptide as a Potential Diagnostic Agent for Colorectal Cancer.

The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase linked to the proliferation, survival, invasion, and metastasis of several types of cancers, including colorectal cancer (CRC), particularly when aberrantly activated. Our study strategically designs peptides derived from interactions between c-Met and the antibody Onartuzumab. By utilizing a cyclic strategy, we achieved significantly enhanced peptide stability and affinity. Our in vitro assessments confirmed that the cyclic peptide HYNIC-cycOn exhibited a higher affinity (KD = 83.5 nM) and greater specificity compared with its linear counterpart. Through in vivo experiments, [99mTc]Tc-HYNIC-cycOn displayed exceptional tumor-targeting capabilities and minimal absorption in nontumor cells, as confirmed by single-photon emission computed tomography. Notably, the ratios of tumor to muscle and tumor to intestine, 1 h postinjection, were 4.78 ± 0.86 and 3.24 ± 0.47, respectively. Comparable ratios were observed in orthotopic CRC models, recording 4.94 ± 0.32 and 3.88 ± 0.41, respectively. In summary, [99mTc]Tc-HYNIC-cycOn shows substantial promise as a candidate for clinical applications. We show that [99mTc]Tc-HYNIC-cycOn can effectively target and visualize c-Met-expressing tumors in vivo, providing a promising approach for enhancing diagnostic accuracy when detecting c-Met in CRC.

Deregulated immune cell recruitment orchestrated by c-MET impairs pulmonary inflammation and fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However, current treatments can only delay disease progression rather than provide a cure. The role of inflammation in PF progression is well-established, but new insights into immune regulation are fundamental for developing more efficient therapies. c-MET signaling has been implicated in the migratory capacity and effector functions of immune cells. Nevertheless, the role of this signaling pathway in the context of PF-associated lung diseases remains unexplored. METHODS: To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases. RESULTS: c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease. CONCLUSIONS: These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.

Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Membrane Receptor-Mediated Disruption of Cellular Homeostasis: Changes in Intracellular Signaling Pathways Increase the Toxicity of Ochratoxin A.

Organisms maintain their cellular homeostatic balance by interacting with their environment through the use of their cell surface receptors. Membrane based receptors such as the transforming growth factor ß receptor (TGFR), the prolactin receptor (PRLR), and hepatocyte growth factor receptor (HGFR), along with their associated signaling cascade, play significant roles in retaining cellular homeostasis. While these receptors and related signaling pathways are essential for health of cell and organism, their dysregulation can lead to imbalance in cell function with severe pathological conditions such as cell death or cancer. Ochratoxin A (OTA) can disrupt cellular homeostasis by altering expression levels of these receptors and/or receptor-associated intracellular downstream signaling modulators and/or pattern and levels of their phosphorylation/dephosphorylation. Recent studies have shown that the activity of the TGFR, the PRLR, and HGFR and their associated signaling cascades change upon OTA exposure. A critical evaluation of these findings suggests that while increased activity of the HGFR and TGFR signaling pathways leads to an increase in cell survival and fibrosis, decreased activity of the PRLR signaling pathway leads to tissue damage. This review explores the roles of these receptors in OTA-related pathologies and effects on cellular homeostasis.

Reversing MET-Mediated Resistance in Oncogene-Driven NSCLC by MET-Activated Wnt Condensative Prodrug.

The amplification of MET is a major cause of acquired resistance to targeted therapy in EGFR-mutant non-small-cell lung cancer (NSCLC), only to be temporarily restrained by the partial efficacy of MET inhibitors. This study reveals that the MET inhibitor has unexpectedly limited efficacy due to amplified MET triggering a strong positive feedback loop in the Wnt/ß-catenin signaling pathway, allowing optimal functionality even when the MET pathway is suppressed again. To test this conjecture and specifically target the Wnt/ß-catenin pathway, a cleverly designed Wnt condensative pro drug called WntSI is developed using reversible supramolecular self-assembly driven by liquidliquid phase separation (LLPS). This process involves a MET/pH-responsive peptide (Tyr-Pep) and a potent Wnt inhibitor known as CA. Upon recognition and phosphorylation of Tyr-Pep by over expressed MET in cells, it disrupts LLPS propensity and facilitates the disintegration of WntSI. Consequently,this enables it to suppress the carcinogenic effect mediated by ß-catenin,effectively overcoming acquired resistance to EGFR-TKIs caused by MET amplification in both cell line-derived and patient-derived tumor xenograft (PDX) mouse models while maintaining exceptional biosecurity. This effective strategy not only suppresses the Wnt/ß-catenin signaling pathway selectively, but also serves as an innovative example for pro-drug development through biologically responsive LLPS.

p53 as a Potential Actionable Target in Myxofibrosarcoma: A Molecular and Pathologic Review of a Single-Institute Series.

Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by high-local recurrence rate, poorly understood molecular pathogenesis, lack of specific prognostic markers, and effective targeted therapies. To gain further insights into the disease, we analyzed a well-defined group of 133 primary MFS cases. Immunohistochemical (IHC) staining for p53, MET, RET, and RB was performed. Twenty-five cases were analyzed by targeted resequencing of known cancer driver hotspot mutations, whereas 66 and 64 MFSs were examined for the presence of genetic variants in TP53 and MET gene, respectively. All clinical, histologic, immunostaining, and genetic variables were analyzed for their impact on 5-years overall survival (OS) and 5-years event-free survival (EFS). In our series, no grade I tumors relapsed and high grade are related to a positive MET immunostaining (P = .034). Both local recurrence (P = .038) and distal metastases (P = .016) correlated to the presence of "single nucleotide variant (SNV) plus copy number variation (CNV)" in TP53. Multivariate analysis revealed that age (>60 years), metastasis at presentation, and positive IHC-p53 signal are risk factors for a poor OS (P = .003, P = .000, and P = .002), whereas age (>60 years), synchronous metastasis, and tumor size (>10 cm) predict an unfavorable 5-years EFS (P = .011, P = .000, and P = .023). Considering the smaller series (n = 66) that underwent molecular screening, the presence of "SNV+CNV" in TP53 represents a risk factor for a worse 5-years EFS (hazard ratio, 2.5; P = .017). The present series confirms that TP53 is frequently altered in MFS (86.4% of cases), appearing to play an important role in MFS tumorigenesis and being a potentially drugable target. A positive p53 immunostainings is related to a poor diagnosis, and it is the presence of a single nucleotide genetic alterations in TP53 that is essential in conferring MFS an aggressive phenotype, thus supporting the use of molecular profiling in MFS to better define the role of p53 as a prognostic factor.

MET Oncogene Targeting for Cancer Immunotherapy.

The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is usurped by cancer cells to induce and sustain the malignant phenotype. MET stands out as one of the most important oncogenes activated in cancer and its inhibition has been explored since the initial era of cancer-targeted therapy. Different approaches have been developed to hamper MET signaling and/or reduce MET (over)expression as a hallmark of transformation. Considering the great interest gained by cancer immunotherapy, this review evaluates the opportunity of targeting MET within therapeutic approaches based on the exploitation of immune functions, either in those cases where MET impairment is crucial to induce an effective response (i.e., when MET is the driver of the malignancy), or when blocking MET represents a way for potentiating the treatment (i.e., when MET is an adjuvant of tumor fitness).