Abstract:
:Numerous tyrosine kinase inhibitors (TKIs) targeting c-Met are currently in clinical trials for several cancers. Their efficacy is limited due to the development of resistance. The present study aims to elucidate this mechanism of c-Met TKI resistance by investigating key mTOR and Wnt signaling proteins in melanoma cell lines resistant to SU11274, a c-Met TKI. Xenografts from RU melanoma cells treated with c-Met TKIs SU11274 and JNJ38877605 showed a 7- and 6-fold reduction in tumor size, respectively. Resistant cells displayed upregulation of phosphorylated c-Met, mTOR, p70S6Kinase, 4E-BP1, ERK, LRP6, and active β-catenin. In addition, GATA-6, a Wnt signaling regulator, was upregulated, and Axin, a negative regulator of the Wnt pathway, was downregulated in resistant cells. Modulation of these mTOR and Wnt pathway proteins was also prevented by combination treatment with SU11274, everolimus, an mTOR inhibitor, and XAV939, a Wnt inhibitor. Treatment with everolimus, resulted in 56% growth inhibition, and a triple combination of SU11274, everolimus and XAV939, resulted in 95% growth inhibition in RU cells. The V600E BRAF mutation was found to be positive only in MU cells. Combination treatment with a c-Met TKI and a BRAF inhibitor displayed a synergistic effect in reducing MU cell viability. These studies indicate activation of mTOR and Wnt signaling pathways in c-Met TKI resistant melanoma cells and suggest that concurrent targeting of c-Met, mTOR, and Wnt pathways and BRAF may improve efficacy over traditional TKI monotherapy in melanoma patients.
journal_name
Cancer Biol Therjournal_title
Cancer biology & therapyauthors
Etnyre D,Stone AL,Fong JT,Jacobs RJ,Uppada SB,Botting GM,Rajanna S,Moravec DN,Shambannagari MR,Crees Z,Girard J,Bertram C,Puri Ndoi
10.4161/cbt.29451subject
Has Abstractpub_date
2014-09-01 00:00:00pages
1129-41issue
9eissn
1538-4047issn
1555-8576pii
29451journal_volume
15pub_type
杂志文章abstract:AIMS:Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy of the oral cavity resulting in severe morbidity and mortality. To date only few proteins have been suggested as potential biomarkers or targets for this type of cancer. Cancerous inhibitor of PP2A (CIP2A) is a protein expressed in epithelial tis...
journal_title:Cancer biology & therapy
pub_type: 评论,杂志文章
doi:10.4161/cbt.10.7.12895
更新日期:2010-10-01 00:00:00
abstract::Melanoma is the deadliest form of skin cancer, which is notoriously aggressive and chemo-resistant, and for which there is little effective treatment available if it goes undetected. Curcumin from the turmeric spice (Curcuma longa) has long been used in Southeast Asian medicine to alleviate ailments and cure an array ...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.11.2.13798
更新日期:2011-01-15 00:00:00
abstract::Arsenic trioxide (As2O3) induces apoptosis in certain types of cancer cells. But the detailed mechanisms of As2O3 efficacy are not completely known. Here we demonstrate that As2O3 has a therapeutic effect on cervical cancer in vitro and in vivo. We investigated the As2O3-induced apoptosis in various cervical cancer ce...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.6.4.3887
更新日期:2007-04-01 00:00:00
abstract::The intrinsic or acquired resistance to multiple drugs (MDR) of cancer cells remains one of the main obstacles for chemotherapy. Development of small molecule targeting to hypoxia inducible factor-1 (HIF-1) has been recently proposed as strategy for treatments of drug-resistant solid tumors. In the present study, emod...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.7.3.5457
更新日期:2008-03-01 00:00:00
abstract::The mitochondrial production of reactive oxygen species has been implicated in the anticancer activity of furanonaphthoquinone. However, the mechanism of the activation remains elusive. In the current study, we found that treatment of HeLa cells with 2-methyl-5(or -8)-hydroxy-furanonaphthoquinone (FNQ13) induces mitoc...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.5.11.3302
更新日期:2006-11-01 00:00:00
abstract::Understanding the biology of breast cancer stem cells and trying new ways to obliterate these cells would be a key step in developing cures for breast cancer. The objective of this study was to investigate the effect of mutant TNFalpha on human breast cancer stem cells derived from MCF7 cell line under the characteriz...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.6.9.4885
更新日期:2007-09-01 00:00:00
abstract::Angiogenesis plays an essential role in tumor growth and metastasis and is a promising target for cancer therapy. We characterized the effects of selective CIAPIN1 inhibition on the angiogenesis gastric cancer cell line SGC7901 by stable transfection of CIAPIN1 siRNA. Our study has been shown that CIAPIN1 play the det...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.8.11.8795
更新日期:2009-06-01 00:00:00
abstract::Nonstop proliferation and vigorous neovascularization are two prominent characteristics of cancer. Antiangiogenic therapy has emerged as an important modality in treatment of solid tumors. Our previous work demonstrated that microparticles derived from apoptotic T-lymphocytes (LMPs) not only reduced the viabilities of...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.10.5.12533
更新日期:2010-09-01 00:00:00
abstract::Polo-like kinase 1 (Plk1) is a key cell cycle regulator that is frequently overexpressed in human hepatocellular carcinomas. Blockade of the Plk1 pathway has been reported to be capable of inducing anti-tumor effect. Here, plasmids containing U6 promoter-driven shRNAs against human Plk1 were constructed and transfecte...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.11.4.14178
更新日期:2011-02-15 00:00:00
abstract::We investigated the role of vasculogenic mimicry (VM) in the progression of prostate cancer (PCa). Ninety-six patients who had undergone prostatectomy for treatment of PCa and for whom a complete record of clinical and follow-up data were available were reviewed. VM and matrix metalloproteinase-2 (MMP-2) were detected...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.19602
更新日期:2012-05-01 00:00:00
abstract::E2F-1, a key transcription factor necessary for cell growth, DNA repair, and differentiation, is an attractive target for development of anticancer drugs in tumors that are E2F "oncogene addicted". We identified a peptide isolated from phage clones that bound tightly to the E2F-1 promoter consensus sequence. The pepti...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.25184
更新日期:2013-08-01 00:00:00
abstract::Overall, NSCLC has a poor 5-year survival and new therapeutic approaches are urgently needed. ERBB-addicted NSCLC that have become resistant to ERBB inhibitors are often refractory to additional therapeutic interventions. The sphingosine-1-phosphate receptor modulator fingolimod (FTY720), approved for the treatment of...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2018.1538616
更新日期:2019-01-01 00:00:00
abstract::The present studies have examined approaches to suppress MCL-1 function in breast cancer cells, as a means to promote tumor cell death. Treatment of breast cancer cells with CDK inhibitors (flavopiridol; roscovitine) enhanced the lethality of the ERBB1 inhibitor lapatinib in a synergistic fashion. CDK inhibitors inter...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.10.9.13273
更新日期:2010-11-01 00:00:00
abstract::Non-small cell lung cancer (NSCLC) remains recalcitrant to effective treatment due to tumor relapse and acquired resistance. Cancer stem cells (CSCs) are believed to be one mechanism for relapse and resistance and are consequently considered promising drug targets. We report that chetomin, an active component of Chaet...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2020.1763147
更新日期:2020-08-02 00:00:00
abstract::Progression of prostate cancer has been associated with EGFR and HER2 activation and to tumor-initiating cells contribution toward chemotherapy resistance. We investigated the efficacy of a dual intervention against EGFR and HER2 to deplete the tumor-initiating cells, optimize the chemotherapy management and prevent t...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2020.1727702
更新日期:2020-05-03 00:00:00
abstract::Colorectal cancer remains the second leading cause of cancer-related mortality in the United States. Although surgical resection is still the primary treatment for colorectal cancer, in recent years, there has been a remarkable progress in the development of new therapies to treat colorectal cancer. Response rates hav...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.6.1.3672
更新日期:2007-01-01 00:00:00
abstract::Heterotypic hybrids created between dendritic cells (DC) and tumor cells represent an efficient approach for loading DC with tumor-associated antigens (TAA) and DC-tumor hybrid vaccines have shown promising outcomes in various preclinical and clinical studies. Conventional DC-tumor hybrid preparations, however, are un...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.3.11.1217
更新日期:2004-11-01 00:00:00
abstract::Antiangiogenic or metronomic chemotherapy, the frequent administration of conventional cytotoxic agents at low doses, is believed to target activated tumor endothelial cells. The mechanisms of action of such regimen remain poorly understood. In the March 2004 issue of Cancer Research, Hamano et al. demonstrated that l...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.3.12.1369
更新日期:2004-12-01 00:00:00
abstract::5-fluorouracil forms classic (covalent, ternary) complexes consisting of thymidylate synthase, fluoro-deoxyuridine monophosphate, and 5,10-methylene tetrahydrofolate. Despite a high pharmacologic interest in the classic complexes formed in cells treated with fluorouracil anticancer agents, the in vivo stability of the...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.5.8.2976
更新日期:2006-08-01 00:00:00
abstract:OBJECTIVES:We herein assessed the influence of Epidermal Growth Factor Receptor (EGFR) gene mutations on EGFR expression levels, downstream mediators such as Akt or ERK, and overall survival in patients with ovarian cancer. STUDY DESIGN:EGFR mutation status was analyzed by direct sequencing in 102 Japanese ovarian can...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.11.1.13877
更新日期:2011-01-01 00:00:00
abstract::Despite its low transfer efficiency, suicide gene therapy with HSV-TK is known for its bystander killing effect. The connexin-based gap junction is believed to mediate the bystander effect. Recently, we found that resveratrol, a polyphenol compound, increased the expression of Cx26 and Cx43, which are connexins and im...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2018.1523094
更新日期:2019-01-01 00:00:00
abstract::The colorectal cancer is the leading contributor of cancer-related mortality. Mammalian target of rapamycin (mTOR), existing in 2 complexes (mTORC1/2), is frequently dysregulated and constitutively activated in colorectal cancers. It represents an important drug target. Here we found that INK-128, the novel ATP-compet...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/15384047.2014.972274
更新日期:2015-01-01 00:00:00
abstract::The Bin1/Amphiphysin2 gene encodes several alternately spliced BAR adapter proteins that have been implicated in membrane-associated and nuclear processes. Bin1 expression is often attenuated during tumor progression and Bin1 splice isoforms that localize to the nucleus display tumor suppressor properties. While these...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.3.12.1232
更新日期:2004-12-01 00:00:00
abstract::Antivascular therapy provides a promising method for anticancer therapy. But targeting to gastric cancer vessels is nonselective due in part to the lack of specific cell-surface receptors identified on target vascular cells. Herein we used in vivo screening of phage displayed peptide library to identify some peptides ...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.3.12.1223
更新日期:2004-12-01 00:00:00
abstract::Rhabdomyosarcoma (RMS) is an aggressive childhood sarcoma with two distinct subtypes, embryonal (ERMS) and alveolar (ARMS) histologies. More effective treatment is needed to improve outcomes, beyond conventional cytotoxic chemotherapy. The pan-histone deacetylase inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), has ...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2018.1529093
更新日期:2019-01-01 00:00:00
abstract::Although daunomycin and adriamycin are considered effective antitumor drugs and have been used in the clinic for over 40 years, their mechanism of action is still a matter of debate. We investigated the influence of daunomycin on interaction between linker or core histones and DNA in live HeLa cells in vitro, using im...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.25328
更新日期:2013-09-01 00:00:00
abstract::KRAS mutational status has been shown to be a predictive biomarker of resistance to anti-EGFR monoclonal antibody (mAb) therapy in patients with metastatic colorectal cancer. We report the spectrum of KRAS mutation in 1506 patients with colorectal cancer and the identification and characterization of rare insertion mu...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.28550
更新日期:2014-06-01 00:00:00
abstract::The recurrence of colorectal cancer after chemotherapy is the leading cause of its high mortality. We propose that elucidating the mechanisms of tumor regrowth after chemotherapy in tumor-bearing mice may provide new insights into tumor relapse in cancer patients. We firstly report the identification of a chemokine, C...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.1080/15384047.2015.1095404
更新日期:2015-01-01 00:00:00
abstract::Colorectal cancer (CRC) is the second most prevalent and deadly cancer worldwide. Due to the mortality and morbidity associated with chemotherapeutic regimes, research is turning to natural product enhancement of the acute apoptotic response to genotoxic carcinogens (AARGC). Although Tyrian purple dye pigments and pre...
journal_title:Cancer biology & therapy
pub_type: 杂志文章
doi:10.4161/cbt.9.5.10887
更新日期:2010-03-01 00:00:00
abstract::Cutaneous T-cell lymphoma (CTCL) displays immunosuppressive properties and phenotypic plasticity. The malignant T cells in CTCL can possess features of immunomodulating regulatory T cells (Treg) and IL-17-producing helper T cells (Th17) depending on the stimuli they receive from antigen presenting cells and other sour...
journal_title:Cancer biology & therapy
pub_type: 杂志文章,评审
doi:10.4161/cbt.12.12.18144
更新日期:2011-12-15 00:00:00