Targeting cMET with INC280 impairs tumour growth and improves efficacy of gemcitabine in a pancreatic cancer model View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-02-19

AUTHORS

Franziska Brandes, Katharina Schmidt, Christine Wagner, Julia Redekopf, Hans Jürgen Schlitt, Edward Kenneth Geissler, Sven Arke Lang

ABSTRACT

BACKGROUND: Expression and activation of the cMET receptor have been implicated in tumor progression and resistance to chemotherapy in human pancreatic cancer. In this regard we assessed the effects of targeting cMET in pancreatic cancer models in vitro and in vivo. METHODS: Human (L3.6pl, BxP3, HPAF-II, MiaPaCa2) and murine (Panc02) pancreatic cancer cell lines, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) were used for the experiments. Furthermore, the human pancreatic cancer cell line MiaPaCa2 with acquired resistance to gemcitabine was employed (MiaPaCa2(G250)). For targeting the cMET receptor, the oral available, ATP-competitive inhibitor INC280 was used. Effects of cMET inhibition on cancer and stromal cells were determined by growth assays, western blotting, motility assays and ELISA. Moreover, orthotopic xenogeneic and syngeneic mouse (BALB-C nu/nu; C57BL/6) models were used to assess in vivo efficacy of targeting cMET alone and in combination with gemcitabine. RESULTS: Treatment with INC280 impairs activation of signaling intermediates in pancreatic cancer cells and ECs, particularly when cells were stimulated with hepatocyte growth factor (HGF). Moreover, motility of cancer cells and ECs in response to HGF was reduced upon treatment with INC280. Only minor effects on VSMCs were detected. Interestingly, MiaPaCa2(G250) showed an increase in cMET expression and cMET inhibition abrogated HGF-induced effects on growth, motility and signaling as well as DFX-hypoxia HIF-1alpha and MDR-1 expression in vitro. In vivo, therapy with INC280 alone led to inhibition of orthotopic tumor growth in xenogeneic and syngeneic models. Similar to in vitro results, cMET expression was increased upon treatment with gemcitabine, and combination of the cMET inhibitor with gemcitabine improved anti-neoplastic capacity in an orthotopic syngeneic model. Immunohistochemical analysis revealed a significant inhibition of tumor cell proliferation (Ki67) and tumor vascularization (CD31). Finally, combination of gemcitabine with INC280 significantly prolonged survival in the orthotopic syngeneic tumor model even when treatment with the cMET inhibitor was initiated at an advanced stage of disease. CONCLUSIONS: These data provide evidence that targeting cMET in combination with gemcitabine may be effective in human pancreatic cancer and warrants further clinical evaluation. More... »

PAGES

71

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12885-015-1064-9

DOI

http://dx.doi.org/10.1186/s12885-015-1064-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1030455566

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25884642


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33 schema:description BACKGROUND: Expression and activation of the cMET receptor have been implicated in tumor progression and resistance to chemotherapy in human pancreatic cancer. In this regard we assessed the effects of targeting cMET in pancreatic cancer models in vitro and in vivo. METHODS: Human (L3.6pl, BxP3, HPAF-II, MiaPaCa2) and murine (Panc02) pancreatic cancer cell lines, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) were used for the experiments. Furthermore, the human pancreatic cancer cell line MiaPaCa2 with acquired resistance to gemcitabine was employed (MiaPaCa2(G250)). For targeting the cMET receptor, the oral available, ATP-competitive inhibitor INC280 was used. Effects of cMET inhibition on cancer and stromal cells were determined by growth assays, western blotting, motility assays and ELISA. Moreover, orthotopic xenogeneic and syngeneic mouse (BALB-C nu/nu; C57BL/6) models were used to assess in vivo efficacy of targeting cMET alone and in combination with gemcitabine. RESULTS: Treatment with INC280 impairs activation of signaling intermediates in pancreatic cancer cells and ECs, particularly when cells were stimulated with hepatocyte growth factor (HGF). Moreover, motility of cancer cells and ECs in response to HGF was reduced upon treatment with INC280. Only minor effects on VSMCs were detected. Interestingly, MiaPaCa2(G250) showed an increase in cMET expression and cMET inhibition abrogated HGF-induced effects on growth, motility and signaling as well as DFX-hypoxia HIF-1alpha and MDR-1 expression in vitro. In vivo, therapy with INC280 alone led to inhibition of orthotopic tumor growth in xenogeneic and syngeneic models. Similar to in vitro results, cMET expression was increased upon treatment with gemcitabine, and combination of the cMET inhibitor with gemcitabine improved anti-neoplastic capacity in an orthotopic syngeneic model. Immunohistochemical analysis revealed a significant inhibition of tumor cell proliferation (Ki67) and tumor vascularization (CD31). Finally, combination of gemcitabine with INC280 significantly prolonged survival in the orthotopic syngeneic tumor model even when treatment with the cMET inhibitor was initiated at an advanced stage of disease. CONCLUSIONS: These data provide evidence that targeting cMET in combination with gemcitabine may be effective in human pancreatic cancer and warrants further clinical evaluation.
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40 schema:keywords ATP-competitive inhibitor INC280
41 DFX-hypoxia HIF-1alpha
42 ELISA
43 HIF-1alpha
44 INC280
45 INC280 impairs activation
46 INC280 impairs tumour growth
47 MDR-1 expression
48 MiaPaCa2
49 Western blotting
50 activation
51 advanced stage
52 analysis
53 anti-neoplastic capacity
54 assays
55 blotting
56 cMET
57 cMET expression
58 cMET inhibition
59 cMET inhibitors
60 cMet receptor
61 cancer
62 cancer cell line MiaPaCa2
63 cancer cell lines
64 cancer cells
65 cancer model
66 capacity
67 cell line MiaPaCa2
68 cell lines
69 cell proliferation
70 cells
71 chemotherapy
72 clinical evaluation
73 combination
74 combination of gemcitabine
75 data
76 disease
77 effect
78 efficacy
79 efficacy of gemcitabine
80 endothelial cells
81 evaluation
82 evidence
83 experiments
84 expression
85 factors
86 gemcitabine
87 growth
88 growth assays
89 growth factor
90 hepatocyte growth factor
91 human pancreatic cancer
92 human pancreatic cancer cell line MiaPaCa2
93 humans
94 immunohistochemical analysis
95 impairs activation
96 impairs tumor growth
97 increase
98 inhibition
99 inhibitor INC280
100 inhibitors
101 intermediates
102 line MiaPaCa2
103 lines
104 minor effect
105 model
106 motility
107 motility assays
108 mouse model
109 murine pancreatic cancer cell lines
110 muscle cells
111 only minor effects
112 orthotopic syngeneic model
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114 orthotopic tumor growth
115 orthotopic xenogeneic
116 pancreatic cancer
117 pancreatic cancer cell line MiaPaCa2
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129 smooth muscle cells
130 stage
131 stromal cells
132 survival
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136 therapy
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139 tumor growth
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