Abstract:
:Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin-sensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS-MAPK-ERK pathway may augment patient responses to cisplatin treatment.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Kong LR,Chua KN,Sim WJ,Ng HC,Bi C,Ho J,Nga ME,Pang YH,Ong WR,Soo RA,Huynh H,Chng WJ,Thiery JP,Goh BCdoi
10.1158/1535-7163.MCT-15-0062subject
Has Abstractpub_date
2015-07-01 00:00:00pages
1750-60issue
7eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-15-0062journal_volume
14pub_type
杂志文章abstract::Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2-targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0046-T
更新日期:2014-08-01 00:00:00
abstract::The KiSS-1 gene has been reported to be a metastasis suppressor gene in human melanoma. The gene product was isolated from human placenta as the ligand of GPR54, a G protein-coupled receptor, and the C-terminally amidated peptide of 54 amino acids is called metastin. The binding of metastin to GPR54 has been shown to ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0521
更新日期:2012-04-01 00:00:00
abstract::To investigate the mechanism by which 5-aminoimidazole-4-carboxamide-1-β-riboside (AICAr) induces apoptosis in multiple myeloma cells, we conducted an unbiased metabolomics screen. AICAr had selective effects on nucleotide metabolism, resulting in an increase in purine metabolites and a decrease in pyrimidine metaboli...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-1042
更新日期:2013-07-01 00:00:00
abstract::The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0454
更新日期:2017-06-01 00:00:00
abstract::Nanotechnology has enabled significant advances in the areas of cancer diagnosis and therapy. The field of drug delivery is a sterling example, with nanoparticles being increasingly used for generating therapeutic formulations of poorly water-soluble, yet potent anticancer drugs. Whereas a number of nanoparticle-drug ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0476
更新日期:2008-12-01 00:00:00
abstract::RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC ce...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-1334
更新日期:2019-11-01 00:00:00
abstract::DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell su...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0535
更新日期:2012-08-01 00:00:00
abstract::Green fluorescent protein (GFP) is employed as a selection marker for gene transduction and to track tumor cells. Transduction of enhanced GFP (eGFP) into human neuroblastoma cell lines via a lentiviral vector significantly sensitized CHLA-20 (wild-type and functional TP53), and to a lesser extent CHLA-90 cells (multi...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2003-09-01 00:00:00
abstract::Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenviron...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0314
更新日期:2008-10-01 00:00:00
abstract::The tumor-associated Tn antigen has been investigated extensively as a biomarker and therapeutic target. Cancer vaccines containing the Tn antigen as a single tumor antigen or as a component of a polyvalent vaccine have progressed into phase I and II clinical trials. One major focus of Tn-based vaccines is the treatme...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0934
更新日期:2009-04-01 00:00:00
abstract::The present study aimed to investigate the therapeutic efficacy of combining vascular endothelial growth factor (VEGF) receptor blockade using tyrosine kinase inhibitor PTK787 with hypoxia for the treatment of hepatocellular carcinoma (HCC). The in vivo effects of the treatments were determined in a rat orthotopic HCC...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0149
更新日期:2006-09-01 00:00:00
abstract::The challenge of developing effective pharmacodynamic biomarkers for preclinical and clinical testing of FGFR signaling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables ac...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0297
更新日期:2016-11-01 00:00:00
abstract::Melanoma is a highly metastatic and deadly disease. An agent simultaneously targeting the COX-2, PI3K/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways that are deregulated in up to 70% of sporadic melanomas might be an effective treatment, but no agent of this type exists. To develop a single drug i...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0492
更新日期:2013-01-01 00:00:00
abstract::Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch-Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordin...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0280
更新日期:2014-12-01 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::Ligand activation of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) and inhibition of cyclooxygenase-2 (COX2) activity by nonsteroidal anti-inflammatory drugs (NSAID) can both attenuate skin tumorigenesis. The present study examined the hypothesis that combining ligand activation of PPARβ/δ with inhibition o...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0820
更新日期:2010-12-01 00:00:00
abstract::TIGIT is an immune checkpoint inhibitor expressed by effector CD4+ and CD8+ T cells, NK cells, and regulatory T cells (Tregs). Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT mAbs has shown in vitro potential to restore T-cell function and therapeutic efficacy in murine tumor models when combined with...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-20-0464
更新日期:2021-01-01 00:00:00
abstract::Several studies have identified silibinin as an anticarcinogenic agent. Recently, we showed that silibinin inhibits cell growth via G1 arrest, leading to differentiation of androgen-dependent human prostate carcinoma LNCaP cells (X. Zi and R. Agarwal, Proc. Natl. Acad. Sci. USA, 96: 7490-7495,1999). Here, we extend th...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-05-01 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::Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis and is a macrophage chemotactic protein. Inhibition of VEGF is beneficial in combination with chemotherapy for some breast cancer patients. However, the mechanism by which inhibition of VEGF affects tumor growth seems to involve more than...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0280
更新日期:2009-07-01 00:00:00
abstract::Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0006-T
更新日期:2013-08-01 00:00:00
abstract::Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2-M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell-cycle progression so that the damaged genome can be repaired. As a t...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-1218
更新日期:2013-10-01 00:00:00
abstract::Rac1 GTPase regulates a variety of signaling pathways that are implicated in malignant phenotypes. Here, we show that selective inhibition of Rac1 activity by the pharmacologic inhibitor NSC23766 suppressed cell growth in a panel of human breast cancer cell lines, whereas it had little toxicity to normal mammary epith...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0906
更新日期:2010-06-01 00:00:00
abstract::Bifunctional antibody fusion proteins engaging effector T cells for targeted elimination of tumor cells via CD3 binding have shown efficacy in both preclinical and clinical studies. Different from such a polyclonal T-cell recruitment, an alternative concept is to engage only antigen-specific T-cell subsets. Recruitmen...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0207
更新日期:2016-09-01 00:00:00
abstract::Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here, w...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0784
更新日期:2018-05-01 00:00:00
abstract::We reported previously that 5-fluorouracil (FUra) efficacy could be enhanced by increasing tumoral thymidine phosphorylase (TP) activity. Potentiated TP yield was achieved by either transfecting cells with human TP gene (A. Evrard et al., Br. J. Cancer, 80: 1726-1733, 1999) or associating FUra with 2'-deoxyinosine (d-...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2001-12-01 00:00:00
abstract::Radiosensitization caused by the poly(ADP-ribose) polymerase (PARP) inhibitor 4-amino-1,8-naphthalimide (ANI) was investigated in 10 asynchronously growing rodent (V79, CHO-Xrs6, CHO-K1, PARP-1+/+ 3T3, and PARP-1-/- 3T3) or human (HeLa, MRC5VI, IMR90, M059J, and M059K) cell lines, either repair proficient or defective...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0418
更新日期:2006-03-01 00:00:00
abstract::The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratifi...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0342
更新日期:2017-11-01 00:00:00
abstract::Activation of beta-catenin is a critical step in the pathogenesis of many common human cancers and is the initiating event in adenocarcinoma of the colon. Because activation of beta-catenin provides a gain-of-function, it is tempting to speculate that specific pharmacological inhibition of activated beta-catenin might...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-12-01 00:00:00
abstract::An ideal therapeutic for cancer would be one that selectively targets to tumor cells, is nontoxic to normal cells, and that could be systemically delivered, thereby reaching metastases as well as primary tumor. Immunoliposomes directed by monoclonal antibody or its fragments are promising vehicles for tumor-targeted d...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-03-01 00:00:00