PHA665752 / Pfizer - LARVOL DELTA

Heterogeneous c-Met Activation in Osteosarcoma Dictates Synergistic Vulnerability to Combined c-Met Inhibition and Methotrexate Therapy. (PubMed, Anticancer Res) - "PHA665752 combined with MTX synergistically inhibits OS cell growth via dual suppression of c-Met signaling (PI3K/AKT, MAPK/ERK). and MTX-mediated cytotoxicity, highlighting the potential of co-targeting overlapping pathways to enhance OS treatment efficacy."

Heterogeneity • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • NOS1

Machine learning-based diagnostic and prognostic models for breast cancer: a new frontier on the clinical application of natural killer cell-related gene signatures in precision medicine. (PubMed, Front Immunol) - "Furthermore, drug sensitivity analysis indicated that high-risk patients were more sensitive to Thapsigargin, Docetaxel, AKT inhibitor VIII, Pyrimethamine, and Epothilone B, while showing higher resistance to drugs such as I-BET-762, PHA-665752, and Belinostat. This study provides a comprehensive analysis of NRGs in BC and establishes reliable ML-based diagnostic and prognostic models. The findings highlight the clinical relevance of NRGs in BC progression, immune regulation, and therapy response, offering potential targets for personalized treatment strategies."

Biomarker • Gene Signature • IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • CD2 • IL21 • PRDX1 • ULBP2

Identification of Ion Channel-Associated Prognostic Biomarkers for Lung Adenocarcinoma. (PubMed, J Environ Pathol Toxicol Oncol) - "The drug prediction results showed that individuals with LUAD in the low-risk group were more sensitive to paclitaxel, BI 2536, pyrimethamine, and VX-680, while individuals with LUAD in the high-risk group to erlotinib, sorafenib, panitumumab, PHA-665752, and roscovitine. In summary, ion channel-related genes can provide valuable information for prognosis assessment and drug treatment of LUAD patients."

Biomarker • IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Impact of age-related dermal microenvironment on keratinocyte skin cancer development (SID 2025) - "Importantly, inhibition of HGF signaling in Col1a2-CCN1 mice, with c-Met inhibitor PHA665752, substantially blocked tumor development following two-stage chemical carcinogenesis (N=4, p<0.01) or oncogenic HRas expression (N=3, p<0.01). Furthermore, mice with fibroblast-specific CCN1 knockout (Pdgfra-CreER; CCN1fl/fl) displayed reduced tumor development following two-stage chemical carcinogenesis (N=5, p<0.01) or chronic exposure to ultraviolet irradiation (UV) (N=6, p<0.01). These findings highlight the critical role of age-related changes in the dermal microenvironment that enable keratinocyte cancer development and advance understanding of the mechanisms involved in the heightened prevalence of skin cancer among older populations."

Genetic Disorders • Oncology • Skin Cancer • CCN1 • COL1A2 • HRAS • PDGFRA

HHLA2 activates c-Met and identifies patients for targeted therapy in hepatocellular carcinoma. (PubMed, J Exp Clin Cancer Res) - "HHLA2 acts as an oncogene in HCC by activating c-Met, promoting tumor progression and metastasis. HHLA2 expression correlates with c-Met activation and predicts poor prognosis in HCC patients. Importantly, HHLA2 can serve as a stratification marker for c-Met inhibitor therapy, potentially enabling a personalized approach to improve therapeutic outcomes in this challenging disease."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • HHLA2 • MET • MMP9

ARID1A loss enhances sensitivity to c-MET inhibition by dual targeting of GPX4 and iron homeostasis, inducing ferroptosis. (PubMed, Cell Death Differ) - "c-MET specific inhibitor PHA-665752 as well as two other FDA-approved drugs, crizotinib and cabozantinib, selectively inhibited the growth of ARID1A-deficient CRC cells in vitro and in xenograft tumor models...Inhibition of c-MET in ARID1A-deficient CRC cells diminishes GPX4 expression, resulting in elevated lipid peroxidation and glutathione depletion, ultimately inducing ferroptosis. This study reveals a novel synthetic lethal relationship between ARID1A and c-MET signaling in promoting ferroptosis and proposes c-MET inhibitors as a potential therapeutic strategy for ARID1A-deficient CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • ARID1A • GPX4 • SLC40A1

c-MET tyrosine kinase inhibitors reverse multidrug resistance in breast cancer cells by targeting ABCG2 transporter. (PubMed, J Pharm Pharmacol) - "c-MET inhibitors hold potential as effective agents for reversing MDR in ABCG2-medicated drug-resistant cancer cells."

Journal • Breast Cancer • Oncology • Solid Tumor • ABCG2 • MET

Calcium-dependent adhesion protein CDH18, a potential biomarker for prognosis in uterine corpus endometrial carcinoma. (PubMed, Front Mol Biosci) - "In the group with high CDH18 expression, the IC50 values for (5Z)-7-Oxozeaenol, AG-014699, CEP-701, Mitomycin C, PD-0325901, PD-0332991, PHA-665752, SL 0101-1, and SN-38 were notably elevated. CDH18 is a novel promising biomarker in UCEC, uniquely associating tumor progression, immune modulation, and chemotherapy resistance, offering enhanced prognostic accuracy and guiding individualized therapeutic strategies for improved patient outcomes."

Biomarker • Journal • Tumor mutational burden • Endometrial Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor • Uterine Cancer • CD8 • CDH18 • MUC16 • TMB

Discovery of PPAR Alpha Lipid Pathway Modulators That Do Not Bind Directly to the Receptor as Potential Anti-Cancer Compounds. (PubMed, Int J Mol Sci) - "We selected two compounds, PHA665752 and NSC3852, to dissect how they kill KAIMRC1 cells compared to the antagonist GW6741...Our findings suggest that these two compounds have opposite effects involving fatty acid oxidation in the KAIMRC1 breast cancer cell line. Although we do not fully understand their mechanism of action, our data provide new insights into the potential role of these compounds in targeting breast cancer cells."

Journal • Breast Cancer • Colon Cancer • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • MRC1 • PPARA

c-MET tyrosine kinase inhibitors reverse drug resistance mediated by the ATP-binding cassette transporter B1 (ABCB1) in cancer cells. (PubMed, 3 Biotech) - "Additionally, the combination of c-MET inhibitors with the chemotherapeutic agent doxorubicin synergistically enhanced cytotoxicity in MDR cells, as evidenced by combination index (CI) values of 0.54 ± 0.08, 0.69 ± 0.1, and 0.85 ± 0.07 for cabozantinib, crizotinib, and PHA665752, respectively...In silico analysis also suggested that the transmembrane domains (TMD) of ABCB1 transporters could be considered potential target for these agents. Our results suggest that c-MET inhibitors can serve as promising MDR reversal agents in ABCB1-medicated drug-resistant cancer cells."

Journal • Oncology • ABCB1 • MET

Prognosis and immunotherapeutic implications of molecular classification of cervical cancer based on immunophenoscore-related genes. (PubMed, J Biomol Struct Dyn) - "cluster2 had higher immune cell infiltration levels and better prognosis, with greater sensitivity to Cyclopamine, Imatinib, MG-13, Paclitaxel, PHA-665752, Rapamycin, Sorafenib, Sunitinib, and VX-680. In contrast, cluster3 had higher TTN and PIK3CA mutations and greater sensitivity to AZ628, Dasatinib, Doxorubicin, HG-6-64-1, JQ12, Midostaurin, PF-562271, TAE684, and WH-4-023. In conclusion, we developed a feasible risk score model based on IPS-related genes for cervical cancer prognosis and identified potential drugs for different cervical cancer subtypes."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • PD-L2 • PIK3CA

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

Cigarette smoke extract induces malignant transformation and DNA damage via c-MET phosphorylation in human bronchial epithelial cells. (PubMed, Ecotoxicol Environ Saf) - "The addition of PHA665752, a specific inhibitor of c-MET, or knock-down with c-MET both attenuated DNA damage, while overexpression of c-MET exacerbated DNA damage. Thus, c-MET phosphorylation may be involved in CSE-induced DNA damage, providing a potential target for intervention in the prevention and treatment of smoking-induced lung diseases."

Journal • Oncology • Pulmonary Disease • Respiratory Diseases • CHEK1 • CHEK2

DRN-CDR: A cancer drug response prediction model using multi-omics and drug features. (PubMed, Comput Biol Chem) - "The drugs such as Tivozanib, SNX-2112, CGP-60474, PHA-665752, Foretinib etc., exhibited low median IC50 values and were found to be effective anti-cancer drugs. The case studies with different TCGA cancer types also revealed the effectiveness of SNX-2112, CGP-60474, Foretinib, Cisplatin, Vinblastine etc. This consistent pattern strongly suggests the effectiveness of the model in predicting CDR."

Journal • Oncology

Co-targeting of c-Met and DNA damage response elicits synergistic effects in pancreatic ductal adenocarcinoma (EACR 2024) - "Material and Methods Cabozantinib, crizotinib and PHA665752 were tested as c-Met inhibitors in combination with olaparib and also doxorubicin, a cytotoxic agent that causes severe DNA damage...Similar results were obtained when c-Met inhibitors were combined with doxorubicin in monolayer and 3D cultures. Conclusion The findings of this study show that combination of cMet inhibitors with olaparib as well as doxorubicin could constitute a reasonable strategy for development of more efficacious therapeutic options in PDAC."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRCA • MET

Correction for Smolen et al., Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. (PubMed, Proc Natl Acad Sci U S A) - No abstract available

Journal • Oncology • MET

PHA-665752's Antigrowth and Proapoptotic Effects on HSC-3 Human Oral Cancer Cells. (PubMed, Int J Mol Sci) - "Importantly, genetic ablation of c-Met caused the reduced growth of HSC-3 cells and decreased Src phosphorylation and HIF-1α expression. Together, these results demonstrate that c-Met is highly activated in HSC-3 human oral cancer cells, and PHA exhibits strong antigrowth, proapoptotic, and antiangiogenic effects on these cells, which are mediated through regulation of the phosphorylation and expression of multiple targets, including c-Met, Src, PKB, mTOR, Mcl-1, and HIF-1α."

Journal • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HIF1A • mTOR

MET receptor serves as a promising target in melanoma brain metastases. (PubMed, Acta Neuropathol) - "We found phospho-METY1234/1235 in a subset of MBM and observed a marked response of brain metastasis-derived cell lines (BMCs) that lacked druggable BRAF mutations or developed resistance to BRAF inhibitors (BRAFi) in vivo to MET inhibitors PHA-665752 and ARQ197 (tivantinib). In summary, the activation of MET receptor in brain colonizing melanoma cells by stromal cell-released HGF may promote tumor self-maintenance and expansion and might counteract ICi therapy. Therefore, therapeutic targeting of MET possibly serves as a promising strategy to control intracranial progressive disease and improve patient survival."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor

Identification of aneuploidy-related gene signature to predict survival in head and neck squamous cell carcinomas. (PubMed, Aging (Albany NY)) - "We classified 3 molecular subtypes for HNSC patients and established an ARS prognostic model, which offered a prospective direction for prognosis in HNSC."

Gene Signature • IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CCR4 • CCR7 • CD79A • ICOS • IL1R1 • ZAP70

Combined immune and DDR pathway classifier: A novel pathway-based classification aimed at tailoring personalized therapies for acute myeloid leukemia patients. (PubMed, Comput Biol Med) - "For patients of IMDDR subtype, we recommend the combination of venetoclax and PHA-665752. A-674563 and dovitinib could be combined with DDR inhibitors to treat patients in IMDDR subtype. Moreover, single-cell analysis revealed that there are more immune cells clustered in the IMDDR subtype and higher number of monocyte-like cells, which exert immunosuppressive effects, in the IMDDR subtype. These findings can be applied for molecular stratification of patients and might contribute to the development of personalized targeted therapies for AML."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Targeting aurora kinase b overcomes acquired resistance to met-tyrosine kinase inhibitor in met-amplified lung cancer (AACR 2023) - "Through high-throughput screening of a custom library of 276 compounds, we found that Aurora kinase B (AURKB) inhibitor, barasertib was more sensitive to the PR-S2 cells than H1993 cells...AURKB knockdown using multiple siRNA sequences increases the sensitivity to PHA665752 in the PR-S2 cells...AURKB inhibition induced BIMEL accumulation and reduced p-BIM expression. Collectively, our study suggests that AURKB activation induces resistance to MET-TKI through anti-apoptosis mechanism with upregulation of STAT3/BCL2 axis in MET-amplified lung cancer cells."

IO biomarker • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKB • BCL2 • BCL2L11 • MET • STAT3

Selective inhibition of c-Met as a novel treatment option in epidermolysis bullosa acquisita (ISID 2023) - "In summary, blocking c-Met by PHA-665752 impairs neutrophil functions and effectively treats experimental EBA. Collectively, our results identify c-Met as potential therapeutic target in the treatment of EBA and related autoantibody-mediated, neutrophil-driven diseases."

Immunology • CXCL8 • ITGB2 • MET • SELL

Dual-targeting therapy against HER3/MET in human colorectal cancers. (PubMed, Cancer Med) - "We established HER3-and/or MET-KO SW1116 cell lines, and HER3/MET-double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti-HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D-colony formation, and in vivo tumor growth in nude mice by SW1116 cells The dual targeting of HER3/MET has potential as CRC therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • ERBB3 • FOXM1 • HGF • NRG1

CD44v6+ Hepatocellular Carcinoma Cells Maintain Stemness Properties through Met/cJun/Nanog Signaling. (PubMed, Stem Cells Int) - "Magnetic activated cell sorting was used to separate the CD44v6+ from CD44v6- cells, and Met levels were regulated using lentiviral particles and the selective Met inhibitor, PHA665752...Further, a cJun binding site was identified 1700 bp upstream of the Nanog transcription start site and mutation of the cJun binding site reduced Nanog expression. In conclusion, the HGF/Met signaling pathway is important for maintenance of stemness in CD44v6+ HCC cells by enhancing expression of cJun, which binds 1700 bp upstream of the Nanog transcription start site."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • NANOG

Possible Mechanisms of Increased Cytotoxic T-Cell Infiltration and Elimination of Metastasis in Pancreatic Cancer with HGF/c-MET Inhibition plus Chemotherapy (APA-Pancreatic 2022) - " In vivo: C57BL/6 mice (n = 8 per group) orthotopically injected with KPC cells + mouse pancreatic stellate cells (mPSC) and two weeks later, treated for 5 weeks with vehicle control (C), HGF inhibitor-ZFH7116 (Hi), c-MET inhibitor-PHA665752 (Ci) or gemcitabine (G) as single, dual and triple combinations. HGF/c-MET inhibition + Gem decreased EMT, stemness, cell proliferation and migration, while increasing apoptosis. These effects may mediate the observed decrease in tumor volume and lack of metastasis in vivo. HGF/c-MET inhibition decreased TGFβ secretion by cancer cells which may explain the previously observed increase in cytotoxic T-cell infiltration in vivo."

Gastroenterology • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CDH1 • IL6 • TGFB1 • VIM