Phase 1 Study of the Selective c-MET Inhibitor, HS-10241, in Patients With Advanced Solid Tumors

Dong, Xiaorong; Li, Xingya; Chen, Jianhua; Ma, Shenglin; Mu, Deguang; Hu, J. F.; Lü, Shun

doi:10.1016/j.jtocrr.2022.100449

Cited by 2 publications

(1 citation statement)

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“…This might be associated with a lack of comprehensive molecular stratification of the patients selected in the study. Another Met inhibitor, HS-10241, which Jiangsu Hansoh Pharmaceutical Co., Ltd., developed, has a very selective and specific inhibitory effect on MET and exhibits the ability to pass the BBB, which makes it suitable for targeting MET amplification/overexpression in various numbers of solid tumors, including GBMs [116]. This small-molecule inhibitor has been evaluated in clinical trials (phases 1 and II) for individuals with NSCLC harboring METex14del mutations.…”

Section: Capmatinib (Inc280mentioning

confidence: 99%

Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions

Al-Ghabkari,

Huang,

Park

2024

Cells

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Brain tumors represent a heterogeneous group of neoplasms characterized by a high degree of aggressiveness and a poor prognosis. Despite recent therapeutic advances, the treatment of brain tumors, including glioblastoma (GBM), an aggressive primary brain tumor associated with poor prognosis and resistance to therapy, remains a significant challenge. Receptor tyrosine kinases (RTKs) are critical during development and in adulthood. Dysregulation of RTKs through activating mutations and gene amplification contributes to many human cancers and provides attractive therapeutic targets for treatment. Under physiological conditions, the Met RTK, the hepatocyte growth factor/scatter factor (HGF/SF) receptor, promotes fundamental signaling cascades that modulate epithelial-to-mesenchymal transition (EMT) involved in tissue repair and embryogenesis. In cancer, increased Met activity promotes tumor growth and metastasis by providing signals for proliferation, survival, and migration/invasion. Recent clinical genomic studies have unveiled multiple mechanisms by which MET is genetically altered in GBM, including focal amplification, chromosomal rearrangements generating gene fusions, and a splicing variant mutation (exon 14 skipping, METex14del). Notably, MET overexpression contributes to chemotherapy resistance in GBM by promoting the survival of cancer stem-like cells. This is linked to distinctive Met-induced pathways, such as the upregulation of DNA repair mechanisms, which can protect tumor cells from the cytotoxic effects of chemotherapy. The development of MET-targeted therapies represents a major step forward in the treatment of brain tumours. Preclinical studies have shown that MET-targeted therapies (monoclonal antibodies or small molecule inhibitors) can suppress growth and invasion, enhancing the efficacy of conventional therapies. Early-phase clinical trials have demonstrated promising results with MET-targeted therapies in improving overall survival for patients with recurrent GBM. However, challenges remain, including the need for patient stratification, the optimization of treatment regimens, and the identification of mechanisms of resistance. This review aims to highlight the current understanding of mechanisms underlying MET dysregulation in GBM. In addition, it will focus on the ongoing preclinical and clinical assessment of therapies targeting MET dysregulation in GBM.

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Section: Capmatinib (Inc280mentioning

confidence: 99%