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Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells.
Tanimoto A
,
Yamada T
,
Nanjo S
,
Takeuchi S
,
Ebi H
,
Kita K
,
Matsumoto K
,
Yano S
.
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Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4)--anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.
Figure 1. 17-DMAG suppresses the growth of EML4-ALK NSCLC cells in the presence of HGF and EGFR ligandsThe EML4-ALK lung cancer cell lines human H2228 and human H3122 were treated with increasing concentrations of alectinib or 17-DMAG, with or without HGF (50 ng/mL), EGF (100 ng/mL), HB-EGF (10 ng/mL), and TGF-α (100 ng/mL), and cell viability was determined after 72 h by MTT assay. Data shown are representative of at least 3 independent experiments. Error bars indicate standard deviation (SD) of triplicate cultures.
Figure 2. HGF-gene transfection resulted in reducing susceptibility of EML4-ALK NSCLC cells to alectinib but not 17-DMAG H2228/Vec(A) or H2228/HGF (B) cells were treated with increasing concentrations of alectinib or 17-DMAG, and cell viability was determined after 72 h by MTT assay. Data shown are representative of at least 3 independent experiments. Error bars indicate SD of triplicate cultures.
Figure 3. 17-DMAG reduced MET protein expression and inhibited downstream pathways, even in the presence of HGFH2228/Vec or H2228/HGF cells were treated with or without alectinib (0.3 μmol/L) for 2 h or 17-DMAG (0.3 μmol/L) for 24 h and then stimulated with or without HGF (50 ng/mL) for 10 minutes. The resultant cells were lysed, and the indicated proteins were detected by immunoblotting. Data shown are representative of at least 3 independent experiments.
Figure 4. 17-DMAG reduced MET protein expression and inhibited downstream pathways, even in the presence of EGFR ligandsH2228 cells were treated with or without alectinib (0.3 μmol/L) for 2 h or 17-DMAG (0.3 μmol/L) for 24 h, and then stimulated with or without EGF (100 ng/mL), HB-EGF (10 ng/mL), and TGF-α (100 ng/mL) for 10 min. The resultant cells were lysed, and the indicated proteins were detected by immunoblotting. Data shown are representative of at least 3 independent experiments.
Figure 5. 17-DMAG induced apoptosis of EML4-ALK NSCLC cells, even in the presence of HGFA. Apoptotic cells were evaluated by the 7-AAD cell viability assay, as described in the Materials and Methods. B. Quantification of apoptotic cells.
Figure 6. 17-DMAG reduced viability of EML4-ALK NSCLC cells, even in the presence of both HGF and TGF-αH2228 and H3122 cells were incubated with or without alectinib (0.1 μmol/L), crizotinib (0.1 μmol/L), and/or HGF (50 ng/mL) and TGF-α (100 ng/mL), and cell viability was determined after 72 h by MTT assay. The percentage of cell viability is shown relative to controls without HGF or TGF-α treatment. *, P < 0.001 (one-way ANOVA). NS, not significant. Data shown are representative of at least 3 independent experiments. Error bars indicate SD of triplicate cultures.
Alexander,
2013 European cancer congress.
2013, Pubmed
Alexander,
2013 European cancer congress.
2013,
Pubmed
Birchmeier,
Met, metastasis, motility and more.
2003,
Pubmed
Blagosklonny,
Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs.
2002,
Pubmed
Camidge,
Treating ALK-positive lung cancer--early successes and future challenges.
2012,
Pubmed
Camidge,
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
2012,
Pubmed
Choi,
EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
2010,
Pubmed
,
Echinobase
Demidenko,
Kinase-addiction and bi-phasic sensitivity-resistance of Bcr-Abl- and Raf-1-expressing cells to imatinib and geldanamycin.
2005,
Pubmed
Doebele,
Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.
2012,
Pubmed
Egorin,
Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats.
2002,
Pubmed
Eiseman,
Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts.
2005,
Pubmed
Engelman,
MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
2007,
Pubmed
Hilmi,
IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin.
2008,
Pubmed
Janku,
Tumor heterogeneity in the clinic: is it a real problem?
2014,
Pubmed
Katayama,
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012,
Pubmed
Koivunen,
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
2008,
Pubmed
Koizumi,
Hsp90 inhibition overcomes HGF-triggering resistance to EGFR-TKIs in EGFR-mutant lung cancer by decreasing client protein expression and angiogenesis.
2012,
Pubmed
Masuya,
The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients.
2004,
Pubmed
Meert,
The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis.
2002,
Pubmed
Montesano,
Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor.
1991,
Pubmed
Natan,
Interplay Between HGF/SF-Met-Ras Signaling, Tumor Metabolism and Blood Flow as a Potential Target for Breast Cancer Therapy.
2014,
Pubmed
Normant,
The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models.
2011,
Pubmed
,
Echinobase
Oxnard,
New targetable oncogenes in non-small-cell lung cancer.
2013,
Pubmed
Sakamoto,
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
2011,
Pubmed
Sasaki,
A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.
2011,
Pubmed
Sasaki,
The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.
2010,
Pubmed
Seto,
CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study.
2013,
Pubmed
Shaw,
Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
2009,
Pubmed
Socinski,
A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer.
2013,
Pubmed
Soda,
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
2007,
Pubmed
,
Echinobase
Straussman,
Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.
2012,
Pubmed
Takezawa,
HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.
2012,
Pubmed
Takezawa,
Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer.
2011,
Pubmed
Tang,
MET nucleotide variations and amplification in advanced ovarian cancer: characteristics and outcomes with c-Met inhibitors.
2014,
Pubmed
Ueki,
Hepatocyte growth factor gene therapy of liver cirrhosis in rats.
1999,
Pubmed
Yamada,
Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells.
2012,
Pubmed
Yano,
Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations.
2008,
Pubmed
Yano,
Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort.
2011,
Pubmed
Yasumoto,
The EGFR ligands amphiregulin and heparin-binding egf-like growth factor promote peritoneal carcinomatosis in CXCR4-expressing gastric cancer.
2011,
Pubmed
Zhang,
Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer.
2012,
Pubmed
de Billy,
Shock about heat shock in cancer.
2012,
Pubmed
