Last, consistent with our previous preclinical studies, 18 an up-regulation of genes related to cellular adhesion, extracellular matrix disassembly, and angiogenesis, mechanisms of invasion and metastases in METex14 were also up-regulated in our METex14 cohort by pathway analysis. Tumor angiogenesis is hypothesized to promote an immunosuppressive environment 45 and may serve as an additional factor in immunotherapy resistance in METex14. ...
这是为何越来越多医生开始对MET靶向药化疗以及免疫加上抗血管生成药的原因
Molecular dynamic simulations revealed that ensartinib exhibited favorable binding to c-MET. Ensartinib was highly effective in inhibiting the kinase activity of the MET exon 14 deletion protein (IC50 = 7.9 nM). Furthermore, ensartinib potently suppressed the MET pathway and the growth of Hs746T cells that were subcutaneously implanted into mice. Most importantly, of 17 patients with 14 different types of MET exon 14 skipping mutations undergoing ensartinib treatment, 1 (6%) showed a complete response, 11 (65%) achieved a partial response, and 4 (24%) exhibited stable disease. Thus, the objective response rate (ORR) was 71% and the disease control rate (DCR) was 94%, and the ORR in MET-TKI naive patients was even higher (12/15, 80%). In 2 patients with brain metastasis without prior brain radiation, we observed one partial response in the brain, while in the other patient the brain lesions were stable for 6 months. The most frequently reported adverse events were rash, peripheral edema, and nausea; however, no fatal adverse events occurred.
These results indicate that significant intertumoral heterogeneity exists within the NF1-P53 and NF1 tumorgrafts that promote resistant to MET inhibition. In comparison, NF1-related MPNSTs with high MET expression and activity (i.e. NF1-MET), significant efficacy of MET inhibition was consistently observed。
关键词 NF1-MET，NF1-tp53
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