Abstract:
:Met-amplified EGFR-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition of EGFR and Met tyrosine kinase activities. PC-9 lung adenocarcinoma cells harboring 15-bp deletions (Del E746_A750) in EGFR exon 19 were treated with increasing concentrations of the Met-TKI PHA665752 and 1 μmol/L gefitinib for 1 year; three resistant clones were established via Met amplification. The three dual-resistance cell lines (PC-9DR2, PC-9DR4, and PC-9DR6, designated as DR2, DR4, and DR6, respectively) exhibited different mechanisms for evading both EGFR and Met inhibition. None of the clones harbored a secondary mutation of EGFR T790M or a Met mutation. Insulin-like growth factor (IGF)/IGF1 receptor activation in DR2 and DR4 cells acted as a bypass signaling pathway. Met expression was attenuated to a greater extent in DR2 than in PC-9 cells, but was maintained in DR4 cells by overexpression of IGF-binding protein 3. In DR6 cells, Met was further amplified by association with HSP90, which protected Met from degradation and induced SET and MYND domain-containing 3 (SMYD3)-mediated Met transcription. This is the first report describing the acquisition of dual resistance mechanisms in NSCLC harboring an activating EGFR mutation to Met-TKI and EGFR-TKI following previous EGFR-TKI treatment. These results might inform the development of more effective therapeutic strategies for NSCLC treatment. Mol Cancer Ther; 15(12); 3040-54. ©2016 AACR.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Yamaoka T,Ohmori T,Ohba M,Arata S,Kishino Y,Murata Y,Kusumoto S,Ishida H,Shirai T,Hirose T,Ohnishi T,Sasaki Ydoi
10.1158/1535-7163.MCT-16-0313subject
Has Abstractpub_date
2016-12-01 00:00:00pages
3040-3054issue
12eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-16-0313journal_volume
15pub_type
杂志文章abstract::Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inh...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0798
更新日期:2013-05-01 00:00:00
abstract::Human epidermal growth factor receptor-2 (HER2) and epidermal growth factor receptor (EGFR) heterodimerize to activate mitogenic signaling pathways. We have shown previously, using MCF7 subcloned cell lines with graded levels of HER2 expression, that responsiveness to trastuzumab and AG1478 (an anti-EGFR agent), varie...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0079
更新日期:2007-10-01 00:00:00
abstract::This conference opened with Franco Muggia, host and principal organizer, thanking Joseph Landolph, co-Chair of the International Scientific Organizing Committee and its members (Franco Muggia, co-Chair, Max Costa, Steven Burakoff, Howard Hochster, Eliezer Huberman, John Bertram, Peter Danenberg, and Richard Moran); th...
journal_title:Molecular cancer therapeutics
pub_type:
doi:10.1158/1535-7163.MCT-08-0731
更新日期:2009-05-01 00:00:00
abstract::Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,多中心研究
doi:10.1158/1535-7163.MCT-19-0681
更新日期:2020-02-01 00:00:00
abstract::The breast-specific antigen alpha-lactalbumin is expressed in >60% of breast cancer tissues. To evaluate the effect of gene therapy for breast cancer by controlling adenovirus replication with human alpha-lactalbumin promoter, we investigated the activity of a 762-bp human alpha-lactalbumin promoter. Alpha-lactalbumin...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0167
更新日期:2005-12-01 00:00:00
abstract::Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also inte...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-04-0328
更新日期:2005-09-01 00:00:00
abstract::B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0449
更新日期:2007-03-01 00:00:00
abstract::NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel small molecule anticancer agent. NB1011 is selectively active against tumor cells expressing high levels of thymidylate synthase (TS), a critical enzyme in DNA biosynthesis. NB1011 is different from the current TS-targeted drugs, ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-04-01 00:00:00
abstract::The oncogenic beta-catenin/T-cell factor (TCF) signal is a common trigger inducing expressions of various cancer-related genes and is activated in various types of human malignancy. The aim of this study was to create an effective double-stranded DNA decoy that would interfere with endogenous TCF hyperactivity in tumo...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0388
更新日期:2006-04-01 00:00:00
abstract::RAV12 is a chimeric antibody that recognizes an N-linked carbohydrate antigen (RAAG12) strongly expressed on multiple solid organ cancers. More than 90% of tumors of colorectal, gastric, and pancreatic origin express RAAG12, and a majority of these tumors exhibit uniform RAAG12 expression. RAV12 exhibits potent cytoto...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0581
更新日期:2007-03-01 00:00:00
abstract::In recent years, HER3 has increasingly been implicated in the progression of a variety of tumor types and in acquired resistance to EGFR and HER2 therapies. Whereas EGFR and HER2 primarily signal through the MAPK pathway, HER3, as a heterodimer with EGFR or HER2, potently activates the PI3K pathway. Despite its critic...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-0515
更新日期:2020-02-01 00:00:00
abstract::miR34a is a tumor-suppressor miRNA that functions within the p53 pathway to regulate cell-cycle progression and apoptosis. With apparent roles in metastasis and cancer stem cell development, miR34a provides an interesting opportunity for therapeutic development. A mimic of miR34a was complexed with an amphoteric lipos...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0209
更新日期:2014-10-01 00:00:00
abstract::Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1 and TGF-β2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma....
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0465
更新日期:2017-06-01 00:00:00
abstract::To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-20-0276
更新日期:2020-08-26 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0959
更新日期:2009-01-01 00:00:00
abstract::Nasopharyngeal carcinoma (NPC) is relatively rare in Western countries but is a common cancer in southern Asia. Many differentially expressed genes have been linked to NPC; however, how to prioritize therapeutic targets and potential drugs from unsorted gene lists remains largely unknown. We first collected 558 upregu...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0966
更新日期:2010-09-01 00:00:00
abstract::Inhibitors of histone deacetylases have been approved for clinical application in cancer treatment. On the other hand, histone acetyltransferase (HAT) inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer, the HATs and coactivators p300 and CBP are upregulated...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0182
更新日期:2011-09-01 00:00:00
abstract::Fas-associated protein with death domain (FADD) is a cytosolic adapter protein essential for mediating death receptor-induced apoptosis. It has also been implicated in a number of nonapoptotic activities including embryogenesis, cell-cycle progression, cell proliferation, and tumorigenesis. Our recent studies have sho...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0362
更新日期:2011-10-01 00:00:00
abstract::Histone modification has emerged as a promising approach to cancer therapy. We explored the efficacy of a novel class of histone deacetylase inhibitors in the treatment of malignant gliomas. Treatment of glioma cell lines with two butyric acid derivatives, pivaloylomethyl butyrate (AN-9) and butyroyloxymethyl butyrate...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0087
更新日期:2005-12-01 00:00:00
abstract::R-roscovitine (seliciclib, CYC202) is a cyclin-dependent kinase inhibitor currently in phase II clinical trials in patients with cancer. Here, we describe its mouse metabolism and pharmacokinetics as well as the identification of the principal metabolites in hepatic microsomes, plasma, and urine. Following microsomal ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2005-01-01 00:00:00
abstract::Bisperoxovanadium (bpV) compounds are irreversible protein tyrosine phosphatase (PTP) inhibitors with a spectrum of activity distinct from that of vanadium salts. We studied the efficacy of a panel of bpVs as antineoplastic agents in vitro and in vivo with a view to investigating phosphatases as potential antineoplast...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2003-10-01 00:00:00
abstract::Arsenic trioxide (As(2)O(3)) has been used successfully in the treatment of acute promyelocytic leukemia. However, effects of As(2)O(3) in normal peripheral blood T cells have not been studied in detail. The purpose of this study was to investigate whether As(2)O(3) would induce apoptosis in normal T cells and therefo...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2003-08-01 00:00:00
abstract::Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryr...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0479
更新日期:2011-03-01 00:00:00
abstract::Measles viruses (MV) are rapidly inactivated by anti-measles neutralizing antibodies, which has limited their clinical performance as oncolytic agents. Here, by substituting the H and F surface glycoproteins of MV with those from the homologous canine distemper virus (CDV) and engineering the CDV H attachment protein ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-20-0134
更新日期:2020-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0305
更新日期:2006-09-01 00:00:00
abstract::Ovarian cancer is the leading cause of death from gynecologic cancer. Often, the disease has spread beyond the ovary to involve the peritoneal cavity and causes ascites. Whereas mammalian target of rapamycin (mTOR) functions to regulate protein translation, cell cycle progression, and metastasis, vascular endothelial ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0237
更新日期:2007-11-01 00:00:00
abstract::The inverse association between a high enterolactone (ENL) concentration in both urine and serum, and the risk of breast cancer found in epidemiological studies suggests a chemopreventive action for ENL. However, no causal relationship has been established in clinical studies or in experimental models for breast cance...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-08-01 00:00:00
abstract::The epithelial-mesenchymal transition (EMT) is a process associated with the metastasis of solid tumors as well as with the acquisition of resistance to standard anticancer modalities. A major initiator of EMT in carcinoma cells is TGF-β, which has been shown to induce the expression of several transcription factors u...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-1007
更新日期:2013-09-01 00:00:00
abstract::To date, there is no effective therapy for hormone-independent prostate cancer. Therefore, as a new strategy for refractory cancer, gene therapy is showing increasing promise. In this study, we attempted to use a nonviral gene transfer system, in vivo electroporation, in prostate cancer cell PC-3 xenografts with the w...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-02-01 00:00:00
abstract::HER2-positive breast cancer is currently managed with chemotherapy in combination with specific anti-HER2 therapies, including trastuzumab. However, a high percentage of patients with HER2-positive tumors do not respond to trastuzumab (primary resistance) or either recur (acquired resistance), mostly due to molecular ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-1172
更新日期:2020-08-01 00:00:00