Their study demonstrated that RAD001, an anti-tumor agent, induces an autophagy-related protein expression that increases autophagy, eventually leading to MET de-phosphorylation, and consequently enhances the chemotherapeutic response (Li N. malignancy interventions. amplification may be the cause of resistance to onartuzumab. Moreover, onartuzumab and emibetuzumab did not achieve satisfactory clinical results in Fexofenadine HCl clinical trials (Shah et al., 2015; Camidge et al., 2016). Further investigation is needed to improve the clinical effect of anti-MET monoclonal antibodies and to understand the mechanisms of resistance against them. TABLE 1 Link between MET alteration and therapeutic resistance. and amplificationBerger et al., 2018Patient with NSCLC with MET exon 14 skippingHER2 amplificationDing et al., 2019Patient with advanced lung malignancy with MET exon 14 skipping mutation and MET exon 5 C526F mutationD1246N mutationJin et al., 2019IL-3 dependent murine pro-B cell collection Ba/F3V1092I/L;amplified adenocarcinoma of the distal esophagus;mutationKwak et al., 2015Patient with metastatic gastric adenocarcinoma with and co-amplificationRTK co-amplificationKwak et al., 2015AS703026 (Pimasertib)Gastric malignancy cell collection GTL-16/MKN-45;and cell collection OE33, MET-addicted EGC cell collection SNU638HER2 overexpressionGastric malignancy cell collection GTL16/SG16;mutationSuzawa et al., 2019EMD1214063Lung carcinoma cell collection H1993;and mutationsLeiser et al., 2015EmibetuzumabGastric malignancy cell collection SNU5PTEN loss, PI3K pathway activationKim et Fexofenadine HCl al., 2019GSK1363089Gastric malignancy cell collection MKN45Elevated the express and phosphorylation of MET, and excessive MET signalingFunakoshi et al., 2013bJNJ-38877605Gastric malignancy cell collection GTL-16/MKN-45;gene promoter to increase the expression of MET at the transcriptional level. The positive opinions between HGF/MET and FOXM1 signaling promotes the growth of pancreatic ductal adenocarcinoma and induces resistance to MET inhibition (Musiani et al., 2014). Specifically, HGF overexpression prospects to MET-TKI resistance through an autocrine mechanism in gastric malignancy cells (Cui et al., 2016). The activated SND1-BRAF fusion protein, caused by an amplified chromosomal rearrangement between 7q32 and 7q34, contains a constitutively active BRAF kinase that increases ERK phosphorylation and consequent hyperactivation of the downstream MAPK pathway, eventually Fexofenadine HCl leading to resistance to Rabbit Polyclonal to OR1L8 MET-TKI (Ahn et al., 2017). A similar end result has been observed in another study, where truncated RAF1 and BRAF were identified as significant determinants of the resistance to MET inhibition in GTL-16 cells (Lee et al., 2012). Some studies have demonstrated that this HGF/MET axis-activated downstream PI3K signaling pathway plays an important role in tumor resistance to MET inhibitors. For instance, Ji et al. (2015) demonstrated that this MET-addicted SNU-5 xenograft model developed resistance to MET inhibitors due to PI3K p110 gene overexpression. A combination of the two inhibitors, PHA665752 and PI-103, exerts a significant synergistic anti-tumor effect on PHA665752-resistant xenografts (Petti et al., 2015). Recently, Kim et al. (2019) showed that increased MET and EGFR hetero-dimerization could result in acquired resistance to capmatinib. Their study indicated that this activation of EGFR signaling and/or genetic alteration of the downstream effector phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are option resistance mechanisms used by capmatinib-resistant NSCLC cell lines. Hence, a combined treatment of MET, EGFR, and PI3K inhibitors may be an effective therapeutic strategy in patients with capmatinib-resistant NSCLC (Ji et al., 2015). Moreover, dysfunction of the PI3K pathway is usually linked to resistance to anti-MET antibodies. Especially, Pollmann et al. (2018) recognized two potential mechanisms of resistance, both including PI3K pathway activation, according to their long-term models of either acquired resistance to the MET-targeting antibody emibetuzumab due to PTEN Fexofenadine HCl loss or increased receptor tyrosine kinase activation through Fexofenadine HCl increased MYC and ERBB3 copy figures. Furthermore, Sym015, a mixture of two monoclonal antibodies that bind to non-overlapping MET epitopes, effectively prevents or reduces these resistances due to its broader mechanism of action (Kim.