Abstract 630: Responses of human pancreatic cancer cells to treatment with insulin-like growth factor receptor (IGF-IR) tyrosine kinase inhibitor NVP-AEW541 alone and in combination with anti-EGFR mAb ICR62 or cytotoxic drugs

2011 ◽  
Author(s):  
Nikolaos Ioannou ◽  
Alan M. Seddon ◽  
Angus Dalgleish ◽  
David Mackintosh ◽  
Helmout Modjtahedi
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Cells ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Cytotoxic Drugs ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

Oral tyrosine kinase inhibitor masitinib in combination with gemcitabine in patients with advanced pancreatic cancer: A multicenter phase II study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4617-4617
Author(s):  
P. Hammel ◽  
F. Mornex ◽  
G. Deplanque ◽  
E. Mitry ◽  
P. Levy ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Survival Rates ◽  
Phase Iii ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Multicenter Phase

4617 Background: Masitinib, a tyrosine kinase inhibitor targeting c-Kit, PDGFR, FGFR3 and affecting the FAK pathway, can enhance the antiproliferative effects of gemcitabine (GEM) in human pancreatic cancer cells. This multicenter phase 2 study aimed to determine the efficacy and safety of masitinib in combination with GEM in the first-line treatment of patients with locally advanced (LAPC) or metastatic (MPC) pancreatic cancer. Methods: Patients received oral masitinib (9 mg/kg/d) and standard weekly infusion of GEM (1,000 mg/m2). Primary endpoint was time-to-progression (TTP). Our hypothesis for efficacy was a TTP over 2.1 months. Secondary endpoints included survival rates, tumor response (RECIST) and clinical benefit. Results: 22 patients, with LAPC (n=9) or MPC (n=13), KPS[80–100]/[70] (18/4) were enrolled and treated with masitinib plus GEM. Median TTP was 6.4 months, well beyond our threshold for efficacy (LAPC: 8.3 months, MPC: 2.7 months, KPS[80–100]: 6.4 months, KPS[70]: 0.8 months). At 12 months, 17% of LAPC and 14% of KPS[80–100] were progression-free; all MPC and KPS[70] patients had progressed. The disease control rate was 73% (LAPC: 89%, MPC: 62%, KPS[80–100]: 89%; KPS[70] patients progressed immediately). Median OS was 7.1 months (LAPC: 8.4 months, MPC: 6.8 months, KPS[80–100]: 8.0 months, KPS[70]: 4.4 months). At 18 months, the survival rate was 23%. However, when considering KPS[80–100] alone, it reached 28%. The 18-months survival rates were similar for LAPC (22%) and MPC (23%). 16% of the 19 patients evaluated experienced clinical benefit (LAPC: 38%, KPS[80–100]: 18%). One patient (5%) presented suspected grade 4 neutropenia. Main suspected grade 3 toxicity were anemia, lymphopenia (23%), leucopenia, neutropenia (18%), asthenia (14%), diarrhea, cytolytic hepatitis, and skin rash (9%). Altogether, the combination masitinib plus GEM did not seem to increase the toxicity commonly reported with GEM alone. Conclusions: The antitumor activity of the combination masitinib plus GEM is very promising and does not present limiting toxicities. Based on those encouraging data, a randomized phase III trial comparing masitinib plus GEM with GEM alone is now actively recruiting patients in the US and in Europe. [Table: see text]

scholarly journals Silencing of the DJ-1 (PARK7) gene sensitizes pancreatic cancer to erlotinib inhibition

2019 ◽  
Author(s):  
Xiangyi He ◽  
Yunwei Sun ◽  
Rong Fan ◽  
jing Sun ◽  
Douwu Zou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Kinase Inhibitor ◽  
Egfr Tyrosine Kinase Inhibitor ◽  
Pancreatic Cancer Cells

Abstract Abstract AIMS: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib, in combination with gemcitabine, has been shown to be a promising therapy in the treatment of pancreatic cancer. Our previous study showed that DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA. The aim of this study was to evaluate whether silencing DJ-1 expression can sensitize pancreatic cancer cells to erlotinib treatment. METHODS: Knockdown of DJ-1 expression, combined with erlotinib treatment, was performed in the pancreatic cancer cell lines BxPC-3 and PANC-1. Cell proliferation was assessed with the CCK-8 assay and BrdU incorporation, while apoptosis was measured using terminal deoxynucleotidyl ransferase (TdT)-mediated dUTP nick-end labeling. RAS activity and activation of the downstream pathways involving AKT and ERK1/2 were explored to determine the underlying mechanism. RESULTS: Knockdown of DJ-1 expression accelerated erlotinib-induced cell apoptosis, and improved the inhibitory effect of erlotinib on pancreatic cancer cell proliferation in vitro and in xenograft tumor growth in vivo. Knockdown of DJ-1 decreased K-RAS expression, membrane translocation, and activity in BxPC-3 cells. Knockdown of DJ-1 also decreased K-RAS, H-RAS, and N-RAS expression in PANC-1 cells. Knockdown of DJ-1 synergistically inhibited AKT and ERK1/2 phosphorylation with erlotinib in pancreatic cancer cells. CONCLUSIONS: DJ-1 may activate the RAS pathway, reinforcing erlotinib drug resistance. Blocking DJ-1 in combination with the EGFR tyrosine kinase inhibitor erlotinib may be an attractive therapeutic target in pancreatic cancer.

scholarly journals Silencing of the DJ-1 (PARK7) gene sensitizes pancreatic cancer to erlotinib inhibition

2019 ◽  
Author(s):  
Xiangyi He ◽  
Yunwei Sun ◽  
Rong Fan ◽  
jing Sun ◽  
Douwu Zou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Kinase Inhibitor ◽  
Egfr Tyrosine Kinase Inhibitor ◽  
Pancreatic Cancer Cells

Abstract Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib, in combination with gemcitabine, has been shown to be a promising therapy in the treatment of pancreatic cancer. Our previous study showed that DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA. The aim of this study was to evaluate whether silencing DJ-1 expression can sensitize pancreatic cancer cells to erlotinib treatment. METHODS: Knockdown of DJ-1 expression, combined with erlotinib treatment, was performed in the pancreatic cancer cell lines BxPC-3, PANC-1 and MiaPACa-2. Cell proliferation was assessed with the CCK-8 assay and BrdU incorporation, while apoptosis was measured using terminal deoxynucleotidyl ransferase (TdT)-mediated dUTP nick-end labeling. RAS activity and activation of the downstream pathways involving AKT and ERK1/2 were explored to determine the underlying mechanism. RESULTS: Knockdown of DJ-1 expression accelerated erlotinib-induced cell apoptosis, and improved the inhibitory effect of erlotinib on pancreatic cancer cell proliferation in vitro and in xenograft tumor growth in vivo . Knockdown of DJ-1 decreased K-RAS expression, membrane translocation, and activity in BxPC-3 cells. Knockdown of DJ-1 also decreased K-RAS, H-RAS, and N-RAS expression in PANC-1 and MiaPACa-2 cells. Knockdown of DJ-1 synergistically inhibited AKT and ERK1/2 phosphorylation with erlotinib in pancreatic cancer cells. CONCLUSIONS: DJ-1 may activate the RAS pathway, reinforcing erlotinib drug resistance. Blocking DJ-1 in combination with the EGFR tyrosine kinase inhibitor erlotinib may be an attractive therapeutic target in pancreatic cancer.

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