Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-α conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC.
Moreover, the treatment of the c-MET inhibitor SGX523, the PI3K inhibitor LY294002, and the Akt inhibitor MK-2206 reduced circFAM53B-mediated oncogenic effects. Conclusively, circFAM53B aggravated glioma progression by up-regulating the c-MET/PI3K/AKT pathway and down-regulating miR-532-3p. Thus, the circFAM53B/miR-532-3p/c-MET/PI3K/AKT axis is a potential treatment target for glioma.
2 years ago
Journal
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MET (MET proto-oncogene, receptor tyrosine kinase) • BCL2 (B-cell CLL/lymphoma 2) • BAX (BCL2-associated X protein) • MIR532 (MicroRNA 532)
These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume)...Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.