Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations

Abstract

Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib. [Cancer Res 2008;68(22):9479-87]

Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC

“…First, target gene alteration, such as gatekeeper mutation or amplification of EGFR, and second, activation of bypass signaling, such as activation of HGF-MET signaling and the PIK3CA mutation (8,10,13,14). We have shown that the FGF2-FGFR1 autocrine loop is an alternative bypass track for acquired resistance to gefitinib in this study (Fig.…”

“…On the other hand, it is important to note that the phosphorylation status of EGFR itself was not affected by FGF2-FGFR1 activation and completely inhibited by gefitinib. Those were also observed in the cases of gefitinib resistance induced by the activation of HGF-MET signaling and considered to be common phenomena in the bypass track activation (10,14). Evaluating the status of EGFR phosphorylation before and after EGFR-TKI treatment may be essential to know whether the mechanism for resistance to EGFR-TKI is due to the activation of bypass track or not.…”

“…One is a second mutation in the EGFR gene itself, EGFR T790M in exon 20 of EGFR (8,9), and the other is amplification of the MET oncogene (10)(11)(12), accounting for approximately 50% and 5% to 20% of acquired resistance to EGFR-TKIs, respectively (8)(9)(10)(11)13). In addition to these mechanisms, various mechanisms of acquiring resistance to EGFR-TKI have been reported, including hepatocyte growth factor (HGF)-MET pathway activation through HGF overexpression (14), epithelial-mesenchymal transition (15), EGFR amplification, and transformation to small cell lung cancer (13). However, approximately 30% of the mechanisms of acquired resistance are unknown (13,16).…”

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

“…The fi rst study showing that HGF can induce gefi tinib resistance in lung adenocarcinomas with EGFR-activating mutations was that by Yano and colleagues ( 63 ), who found that HGF acts by restoring PI3K/AKT activation via phosphorylation of MET (but not of EGFR or HER3); moreover, they showed that strong immunoreactivity for HGF was detected in patients displaying primary or secondary resistance to gefi tinib. The same authors subsequently found that high HGF immunohistochemical reactivity was present in 29% of nonresponding patients, and that HGF expression was signifi cantly higher in tumors with acquired resistance than in sensitive ones ( 64 ).…”

Prospective Study of Gefitinib Readministration After Chemotherapy in Patients With Advanced Non–Small-Cell Lung Cancer Who Previously Responded to Gefitinib

“…Although several possible mechanisms of secondary acquired EGFR mutations 11,12 or other unrelated pathways to EGFR genotypes 13 were reported, successful strategies for overc oming the resistance to EGFR-TKI have yet to be established . [14][15][16] Thus, the development of a novel and possible therapeutic strategy for patients with resistance to EGFR-TKI is an important clinical issue in medical oncology.…”