SU11274 / Pfizer - LARVOL DELTA

Dual blockage of P-cadherin and c-Met synergistically inhibits the growth of head and neck cancer. (PubMed, Cell Oncol (Dordr)) - "Our study uncovered a previously unknown aspect of P-cadherin-mediated c-Met regulation. The enhanced activation of c-Met/STAT3 following P-cadherin inhibition could be responsible for the survival of resistant tumor cells. Therefore, dual inhibition of P-cadherin and c-Met may be an effective approach for treating HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CDH3 • MET • STAT3

Investigating the efficacy of immune checkpoint inhibitors in clear cell renal cell carcinoma based on methylation cross talk scoring. (PubMed, Medicine (Baltimore)) - "Our findings indicate that patients with a low score may be more likely to respond to immunotherapy, whereas patients with a high score may be more sensitive to targeted therapy, such as RITA, Pazopanib, Irlotinib, SU-11274, BRD-K16762525, and FCCP. In conclusion, the score model can serve as a valuable biomarker to guide clinical selection of immunotherapy and targeted drugs and help to improve personalized clear cell renal cell carcinoma treatment."

Biomarker • Checkpoint inhibition • IO biomarker • Journal • Genito-urinary Cancer • Oncology • Solid Tumor

The impact of c-Met inhibition on molecular features and metastatic potential of melanoma cells. (PubMed, Neoplasma) - "In this study, we investigated the influence of three c-Met inhibitors, SU11274, crizotinib, and PHA665752, on molecular characteristics, tumorigenicity, and metastatic behavior in three human melanoma cell lines, M4Beu, EGFP-A375 and its metastatic variant, EGFP-A375/Rel3 (Rel3). The increased tumorigenicity of the Rel3 cells following the SU11274 treatment correlated with the elevated phosphorylation of Akt, p70 S6 and RSK kinases. Our results demonstrate pleiotropic changes induced by small-molecule inhibitors of receptor tyrosine kinases in melanoma cell lines."

Journal • Metastases • Melanoma • Oncology • Solid Tumor • CD133 • NANOG • PROM1

Liver-specific metastasis is recapitulated in a zebrafish larval xenograft model that mimics the tumor microenvironment (EACR 2024) - "Both cell types exhibited higher liver metastasis in the zebrafish compared to control SNU449 cells treated with c-Met inhibitor SU11274, or naive SNU 398 cells...The findings reported here indicate that zebrafish liver microenvironment induces invasion of HCC and CRC cells that are present in the vasculature. Moreover, induction of fatty liver in the larvae affects the metastasis rate.Conclusion The zebrafish hepatic metastatic model presented here offers an intact organism model to study liver preference of metastatic cells."

Preclinical • Tumor microenvironment • Colorectal Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Using network pharmacology to discover potential drugs for hypertrophic scars. (PubMed, Br J Dermatol) - "ITGB1 and TGF-β signaling pathways are important for hypertrophic scar formation. Crizotinib could serve as a potential drug for hypertrophic scars."

Journal • Fibrosis • Immunology • ITGB1 • TGFB1

Hepatocyte growth factor promotes retinal pigment epithelium cell activity through MET/AKT signaling pathway. (PubMed, Int J Ophthalmol) - "HGF enhances cellular viability, proliferation, and migration in RPE cells through the MET/AKT signaling pathway, whereas this enhancement is suppressed by the MET inhibitor SU11274. HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival."

Journal • AKT1 • HGF

EGFR and mTOR signaling facilitate RET-independent resistance to selective RET-TKIs (AACR 2024) - "To determine whether EGFR or MET signaling facilitate RET inhibitor resistance, LC-2/ad and NCCE-TH1101 (KIF5B-RET) NSCLC cells were treated with increasing concentrations of selpercatinib or pralsetinib with or without ligands for these receptors, EGF or HGF respectively, and after five days cell viability was measured by CellTiter Glo...Next, to evaluate whether blockade of EGFR or MET signaling could enhance the activity of RET inhibitors, we treated LC-2/ad and NCCE-TH1101 cells with RET TKIs alone or in combination with the EGFR TKI erlotinib or poziotinib, or the MET inhibitor SU11274...We observed that treatment of LC-2/ad and NCCE-TH1101 cells with an mTOR inhibitor (everolimus) or a MEK inhibitor (trametinib) in combination with RET TKIs increased the anti-tumor activity or RET inhibitors...RET TKI resistant cells were sensitive to mTOR or MEK inhibitors in combination with RET TKIs. Collectively, our findings indicate that in RET-fusion positive NSCLC tumor..."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCDC6 • HER-2 • KIF5B • RET

Hypoxia preconditioning of human amniotic mesenchymal stem cells enhances proliferation and migration and promotes their homing via the HGF/C-MET signaling axis to augment the repair of acute liver failure. (PubMed, Tissue Cell) - "Hypoxic preconditioning depicted no impact on the morphology and phenotype features of the human amniotic mesenchymal stem cells, but it can promote their proliferation, migration, anti-apoptotic effect, and homing rate and improve the repair of acute liver failure, which might be mediated by the HGF/c-Met signaling axis."

Journal • Hepatology • Liver Failure • Transplantation • CD31 • CD34 • CXCR4 • ENG • MET • PECAM1 • PTPRC • THY1

The anti-tumor effects of AZD4547 on ovarian cancer cells: differential responses based on c-Met and FGF19/FGFR4 expression. (PubMed, Cancer Cell Int) - "This study showed that AZD4547 has significant anti-cancer effects in drug-sensitive cells and PDX models but not in drug-resistant EOC cells. In drug-resistant cells, the expression level of c-Met or FGF19/FGFR4 may be a predictive biomarker for AZD4547 treatment response, and a combination strategy of drugs targeting c-Met or FGF19/FGFR4 together with AZD4547 may be an effective therapeutic strategy for EOC."

Journal • Oncology • Ovarian Cancer • Solid Tumor • FGF19 • FGFR4 • MET

THE ANTI-CANCER EFFECTS OF AZD4547 ON OVARIAN CANCER CELLS: DIFFERENTIAL RESPONSES BASED ON FGF19 AND C-MET EXPRESSIONS (IGCS 2023) - "AZD4547 significantly decreased cell survival and migration in EOC cells except for A2780- CP20 and SKOV3-TR cells. AZD4547 significantly decreased tumor weight in xenograft models of EOC cells and in a PDX model established with platinum-sensitive tumors but not in A2780-CP20 and SKOV3- TR. Expression of c-Met in SKOV3-TR cells was higher than other cells and combination of SU11274 and AZD4547 increased cell death."

Oncology • Ovarian Cancer • Solid Tumor • FGF19 • FGFR1 • FGFR4 • MET

Adaptive c-Met-PLXDC2 Signaling Axis Mediates Cancer Stem Cell Plasticity to Confer Radioresistance-associated Aggressiveness in Head and Neck Cancer. (PubMed, Cancer Res Commun) - "Therapeutically, the addition of SU11274, a selective and potent c-Met inhibitor, to radiation induces tumor shrinkage and limits tumor metastasis to lymph nodes in an orthotopic mouse model. Collectively, these significant findings not only demonstrate a novel mechanism underpinning radioresistance-associated aggressiveness but also provide a possible therapeutic strategy to target radioresistance in patients with HNSCC. This work provides novel insights into c-Met-PLXDC2 signaling in radioresistance-associated aggressiveness and suggests a new mechanism-informed therapeutic strategy to overcome failure of radiotherapy in patients with HNSCC."

Cancer stem • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MET

Met confers radioresistance‐associated aggressiveness through enhancing PLXDC2-mediated cancer stem cell plasticity (AACR 2023) - "Therapeutically, a combination of the c-Met selective inhibitor SU11274 with radiation remarkably induces tumor shrinkage and constrains tumor metastasis to lymph nodes in vivo. Our study is novel in being the first to explore the role and mechanism of the c-Met-PLXDC2 axis in radioresistance-associated HNSCC aggressiveness and the first to our knowledge to evaluate how to take advantage of blocking this signaling to overcome radioresistance in preclinical mouse models of HNSCC."

Cancer stem • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MET

Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide. (PubMed, World J Gastroenterol) - "PTHrP acts through the Met pathway in CRC cells and regulates Met expression in a CRC animal model. More basic and clinical studies are needed to further evaluate the PTHrP/Met relationship."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MET • PTHLH

Sensitizing Liver Cancer Cells to c-Met Inhibitors via Targeting Neddylation (EACR 2022) - "MLN4924 and SU11274 were used as specific inhibitors for NEDD8 conjugation and c-Met activation, respectively. Analysis of tumor vs. non-tumor tissues in chow and HFHS mice identified high NEDD8 expression and there is a significant change in activation status of c-Met in tumor tissues. Conclusion Preventing c-Met neddylation specifically in liver cancer patients could serve as a precisely targeted therapy method in patients with aggressive tumor."

Diabetes • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • ABCB4

β-adrenergic receptor promotes liver regeneration partially through crosstalk with c-met. (PubMed, Cell Death Dis) - "Inhibition of c-met with SU11274 or ERK with U0126 decreased βAR overexpression-induced hepatocyte proliferation. Our findings revealed that βAR might act as a critical mediator regulating liver regeneration by crosstalk with c-met and activation of ERK signaling."

Journal • Oncology • MET

Interleukin-1β and exosomal M6PR secreted by serglycin-overexpressing esophageal cancer cells instigate fibroblasts and endothelial cells to promote esophageal cancer progression (AACR 2022) - "Treatment with SU11274, a c-Met (the receptor of HGF) inhibitor, attenuated the proliferation of ESCC cells co-cultured with HEF, which further indicates that IL-1β-induced HGF from HEF plays a significant role in the tumor microenvironment...[This study was supported by Research Grants Council of the Hong Kong SAR, China, GRF Project No. 17100819]"

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Oncology • Squamous Cell Carcinoma • FAP • HGF • IL18 • IL1B • ITGA5 • MET • NOTCH2 • TENM2 • TNFA

Curcumin Inhibits HGF-Induced EMT by Regulating c-MET-Dependent PI3K/Akt/mTOR Signaling Pathways in Meningioma. (PubMed, Evid Based Complement Alternat Med) - "In addition, treatment of human malignant meningioma cells with the tyrosine protein kinase (c-MET) inhibitor (SU11274) or the phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) suppressed HGF-induced migration and EMT. These findings indicate that HGF regulates EMT in human malignant meningioma cells through c-MET/PI3K/Akt/mTOR modulation. In conclusion, curcumin inhibits HGF-induced EMT by targeting c-MET and subsequently blocking the PI3K/Akt/mTOR pathway."

Journal • Brain Cancer • Immunology • Meningioma • Oncology • Solid Tumor • Transplantation • MET

EGFR Alterations Influence the Cetuximab Treatment Response and c-MET Tyrosine-Kinase Inhibitor Sensitivity in Experimental Head and Neck Squamous Cell Carcinomas. (PubMed, Pathol Oncol Res) - "Interestingly, the cetuximab-resistant R521K tumors were successfully treated with c-MET tyrosine kinase inhibitor SU11274. Our results suggest that HNSCC cell line expressing the R521K mutant form of EGFR does not respond well to cetuximab treatment in vitro or in vivo, but hopefully might be targeted by c-MET tyrosine kinase inhibitor treatment."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • MET

[VIRTUAL] HGF/C-MET SIGNALING PROMOTE ANGIOGENESIS THROUGH CXCL16 IN RHEUMATOID ARTHRITIS (EULAR 2021) - "c-Met signal inhibition by SU11274 suppressed TNF-α stimulation-enhanced CXCL16 production by RA FLSs in a dose-dependent manner... HGF is produced by inflammation in the RA synovium, and activates angiogenesis through its own potent angiogenic effect and enhanced production of CXCL16 in the synovium. These results indicate that a strategy targeting c-Met signalling may be important for resolving treatment-resistant RA."

Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • MET • TNFA

Consequences of extracellular alterations of EGFR on cetuximab therapy in HNSCC (PubMed, Magy Onkol) - "This selectivity was not reflected in immunophenotype or survival data of HNSCC patients, suggesting a more complex mechanism behind. Interestingly, c-Met inhibitor SU11274 was more effective in cetuximab-resistant, EGFR R521K heterozygous cells and xenografts, raising the possible importance of simultaneous targeting of the two receptors."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR

Hepatocyte growth factor overexpression promotes osteoclastogenesis and exacerbates bone loss in CIA mice. (PubMed, J Orthop Translat) - "SU11274, a selective small molecule blocker of c-Met, impeded the effect of HGF on osteoclastogenesis and bone resorption...Inhibition of HGF/c-Met could effectively alleviate pathological bone loss and inflammatory symptoms in CIA mice. HGF/c-Met may be used as a new target for the treatment of bone loss in RA."

Journal • Immunology • Inflammatory Arthritis • Osteoporosis • Rheumatoid Arthritis • Rheumatology • HGF • MAPK8 • MET

Clear cell renal cell carcinoma resistance to RTKs inhibitors is mediated by c-Met receptor and MCPIP1 (AACR 2018) - "Several hypotheses have been proposed regarding the mechanisms underlying resistance to RTKs inhibitors, but the precise pathways have not yet been fully elucidated.AimThe main objective of our study was to determine the role of c-Met and anti-inflammatory protein MCPIP1 in the acquisition of resistance to RTKs inhibitors in ccRCC.Materials and methodsccRCC cell lines (Caki-1 and Caki-2) as well as normal epithelial cell lines (Hek293, RPTEC/TERT1) were treated with sunitinib, sorafenib or SU11274 constantly for 24h, 1 and 3 weeks. Proposed research may help in understanding the mechanisms responsible for tumor resistance to targeted therapy. Obtained results may contribute to increased understanding of the biology of clear cell renal cell carcinoma, which in the future may help in identifying new, more effective therapeutic purposes or improving existing ones.AcknowledgmentThis study was supported by research grant from the National Science Centre 2013/09/D/NZ/00249,..."

Renal Cell Carcinoma

CUL4B promotes aggressive phenotypes of renal cell carcinoma via upregulating c-Met expression. (PubMed, Int J Biochem Cell Biol) - "We also showed that CUL4B overexpression significantly accelerated xenograft tumor growth, and administration of SU11274 could also abrogate the accelerated tumor growth induced by CUL4B overexpression in vivo. These findings shed light on the contribution of CUL4B to tumorigenesis in RCC via activating c-Met signaling and its therapeutic implications in RCC patients."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • MET

MET promotes the proliferation and differentiation of myoblasts. (PubMed, Exp Cell Res) - "Furthermore, this study demonstrated that SU11274, an inhibitor of MET kinase activity, suppressed myoblast differentiation, suggesting that MET regulated the expression of myogenic regulatory factors (MRFs) and of desmin through the classical tyrosine kinase pathway. On the basis of the above findings, our work confirmed that MET promoted the proliferation and differentiation of myoblasts, deepening our understanding of the molecular mechanisms underlying muscle development."

Journal

MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in gastric cancer cells. (PubMed, Cancer Med) - "From these data, we infer that MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in GC cells and suggest that MACC1 may be a therapeutic target for GC immunotherapy."

IO Biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor