Abstract | BACKGROUND: METHODS: We utilized the human MHCC97-H c-Met positive (c-Met+) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses. RESULTS: We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone. CONCLUSION: c-Met inhibition monotherapy is not sufficient to eliminate c-Met+ HCC tumor growth. Inhibition of both c-Met and EGFR oncogenic pathways provides superior suppression of HCC tumor growth. Thus, combination of c-Met and EGFR inhibition may represent a superior therapeutic regimen for c-Met+ HCC.
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Authors | Steven N Steinway, Hien Dang, Hanning You, C Bart Rountree, Wei Ding |
Journal | PloS one
(PLoS One)
Vol. 10
Issue 5
Pg. e0128159
( 2015)
ISSN: 1932-6203 [Electronic] United States |
PMID | 26000702
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
- Indoles
- Sulfones
- Hepatocyte Growth Factor
- ERBB3 protein, human
- ErbB Receptors
- Proto-Oncogene Proteins c-met
- Receptor, ErbB-3
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Topics |
- Carcinoma, Hepatocellular
(drug therapy, metabolism, pathology)
- Cell Line, Tumor
- Cell Survival
(drug effects, physiology)
- ErbB Receptors
(genetics, metabolism)
- Female
- Hepatocyte Growth Factor
(genetics, metabolism)
- Humans
- Indoles
(pharmacology)
- Liver Neoplasms
(drug therapy, metabolism, pathology)
- Male
- Proto-Oncogene Proteins c-met
(antagonists & inhibitors, genetics, metabolism)
- Receptor, ErbB-3
(genetics, metabolism)
- Signal Transduction
(drug effects, physiology)
- Sulfones
(pharmacology)
|