Met Kinase Inhibitor E7050 Reverses Three Different Mechanisms of Hepatocyte Growth Factor–Induced Tyrosine Kinase Inhibitor Resistance in EGFR Mutant Lung Cancer

Abstract

Translational relevanceHepatocyte growth factor (HGF) is involved in at least three important steps of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance in EGFR mutant lung cancer, inducing resistance to reversible EGFR-TKIs by restoring Met/Gab1/PI3K/Akt pathways, inducing resistance to next-generation EGFR-TKIs (irreversible TKI and mutant-selective EGFR-TKI), and accelerating the emergence of EGFR-TKI-resistant clones by continuous exposure to HGF. Therefore, HGF may be an ideal target for overcoming EGFR-TKI resistance in EGFR mutant lung cancer.

Amiloride sensitizes human pancreatic cancer cells to erlotinib in vitro through inhibition of the PI3K/AKT signaling pathway

“…The viability of Bxpc-3, PANC-1, Aspc-1, and CFPAC-1 pancreatic cancer cells treated with amiloride (10, 30, and 100 µmol/L), erlotinib (3, 10, and 30 µmol/L), or their combination was determined by the MTT assay ( Figure 1A). Amiloride (10,30, and 100 µmol/L) significantly enhanced the erlotinib-induced inhibition of tumor cell growth in a concentration-dependent manner in a heterogeneous group of pancreatic cancer cell lines, including one harboring a wild-type K-Ras (Bxpc-3), two lines with a K-Ras G12D mutation (PANC-1 and Aspc-1), and another cell line harboring a K-Ras G12V mutation (CFPAC-1). We also analyzed the interaction between amiloride and erlotinib using Chou-Talalay's synergism analysis, a widely used method to analyze the synergy interaction in combination therapies.…”

“…Inhibition of the PI3K/AKT pathway by blocking Met or using a PI3K inhibitor restores HGFinduced mechanisms of EGFR-TKI resistance to NSCLC [9,10] . Similarly, inhibition of the PI3K/AKT pathway also potentiated the cytotoxicity of EGFR-TKIs in breast cancer cells [11,12] .…”

Norcantharidin combined with EGFR-TKIs overcomes HGF-induced resistance to EGFR-TKIs in EGFR mutant lung cancer cells via inhibition of Met/PI3k/Akt pathway

“…According to many studies, the activation of Met and the downstream PI3K/Akt pathway lead to the resistance to EGFR-TKIs in EGFR mutant lung cancer induced by HGF [8,10,23,24]. Therefore, using western blotting, we detected the effects of NCTD on signal transduction in PC-9/HCC827 cells, which were exposed to HGF.…”

MET overexpression and gene amplification in NSCLC: a clinical perspective

“…[88][89][90][91] However, the occurrence of similarly dramatic responses in NSCLC cases harboring an ALK rearrangement shifted the enthusiasm of researchers towards clinical development of the drug in this molecularly defined setting. 16 Other non-selective tyrosine kinase inhibitors targeting MET, RET, VEGF, KIT, FLT3, and RON, such as cabozantinib (XL184, Exelixis, San Francisco, CA, USA), 107 foretinib (XL880, Exelixis), 108,109 and golvatinib (E7050, Eisai, Tokyo, Japan) 110,111 have been extensively evaluated, and several Phase I-III studies of these new agents are currently ongoing in patients with different type of malignancies such as gastric and medullary thyroid cancer, glioblastoma, and renal cell carcinoma.…”

“…115,116 Golvatinib also inhibits MET and VEGFR, and in vitro models have demonstrated the ability of this agent to prevent emergence of resistance to EGFR tyrosine kinase sustained by HGF. 110 A Phase I study in adults with advanced solid tumors established 400 mg daily as the recommended dose, while fatigue, diarrhea, nausea/vomiting, and increased transaminase levels were the typical toxicities. 111 Early clinical trials of MGC D265 and ANG707, two of the newest non-selective MET inhibitors, have just started recruitment, and it is planned to give these agents as monotherapy or in combination with erlotinib.…”