Cotargeting MAPK and PI3K signaling with concurrent radiotherapy as a strategy for the treatment of pancreatic cancer.

Abstract:

:There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS-activating mutations, which are found in more than 90% of pancreatic adenocarcinomas, drive tumor dependency on the Ras/MAPK and Akt signaling pathways. Radiation is currently being explored as a component of the standard treatment regimen for pancreatic cancer. This study's purpose was to test the hypothesis that MAP kinase kinase (MEK or MAP2K) inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the mitogen-activated protein kinase (MAPK) and Akt pathways in response to radiation in multiple pancreatic tumor cell lines. Small molecule inhibitors of MEK (PD0325901) and Akt (API-2) were subsequently evaluated for their radiosensitizing potential alone and in combination. In vivo efficacy was tested in subcutaneous MIA-PaCa2 xenografts. Phosphorylated levels of extracellular signal-regulated kinase (ERK)-1/2 and Akt were found to increase in response to radiation treatment in our pancreatic tumor cell line panel. MEK inhibitor-induced radiosensitization was observed in vitro and in vivo. The further addition of an Akt inhibitor to the MEK inhibitor/radiation regimen resulted in enhanced therapeutic gain as determined by increased radiosensitization and tumor cell death. In conclusion, MEK inhibition results in growth arrest, apoptosis, and radiosensitization of multiple preclinical pancreatic tumor models, and the effects can be enhanced by combination with an Akt inhibitor. These results provide rationale for further testing of a treatment regimen in pancreatic cancer that combines MEK inhibition with radiation, optimally in conjunction with Akt inhibition.

journal_name

Mol Cancer Ther

authors

Williams TM,Flecha AR,Keller P,Ram A,Karnak D,Galbán S,Galbán CJ,Ross BD,Lawrence TS,Rehemtulla A,Sebolt-Leopold J

doi

10.1158/1535-7163.MCT-12-0098

subject

Has Abstract

pub_date

2012-05-01 00:00:00

pages

1193-202

issue

5

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-12-0098

journal_volume

11

pub_type

杂志文章
  • A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo.

    abstract::The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivatio...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-0131

    authors: Liu Y,Cao Y,Zhang W,Bergmeier S,Qian Y,Akbar H,Colvin R,Ding J,Tong L,Wu S,Hines J,Chen X

    更新日期:2012-08-01 00:00:00

  • A Spatio-Temporal Model of Macrophage-Mediated Drug Resistance in Glioma Immunotherapy.

    abstract::The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0634

    authors: Zheng Y,Bao J,Zhao Q,Zhou T,Sun X

    更新日期:2018-04-01 00:00:00

  • The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells.

    abstract::The expression of cyclooxygenase (COX)-2 is increased in human cancers including cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms of the selective COX-2 inhibitor celecoxib in the growth control of human cholangiocarcinoma cells. Immunohistochemical analysis using human cholangiocarcin...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Wu T,Leng J,Han C,Demetris AJ

    更新日期:2004-03-01 00:00:00

  • Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2'-deoxycytidine.

    abstract::DNA cytosine methylation plays a considerable role in normal development, gene regulation, and carcinogenesis. Hypermethylation of the promoters of some tumor suppressor genes and the associated silencing of these genes often occur in certain cancer types. The reversal of this process by DNA methylation inhibitors is ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0172

    authors: Chuang JC,Yoo CB,Kwan JM,Li TW,Liang G,Yang AS,Jones PA

    更新日期:2005-10-01 00:00:00

  • Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies.

    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

    authors: Preillon J,Cuende J,Rabolli V,Garnero L,Mercier M,Wald N,Pappalardo A,Denies S,Jamart D,Michaux AC,Pirson R,Pitard V,Bagot M,Prasad S,Houthuys E,Brouwer M,Marillier R,Lambolez F,Marchante JR,Nyawouame F,Carter MJ

    更新日期:2021-01-01 00:00:00

  • Dibenzophenanthridines as inhibitors of glutaminase C and cancer cell proliferation.

    abstract::One hallmark of cancer cells is their adaptation to rely upon an altered metabolic scheme that includes changes in the glycolytic pathway, known as the Warburg effect, and elevated glutamine metabolism. Glutaminase, a mitochondrial enzyme, plays a key role in the metabolism of glutamine in cancer cells, and its inhibi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-11-0942

    authors: Katt WP,Ramachandran S,Erickson JW,Cerione RA

    更新日期:2012-06-01 00:00:00

  • Sensitizing hormone-refractory prostate cancer cells to drug treatment by targeting 14-3-3sigma.

    abstract::Advanced and hormone-refractory prostate cancer has long been considered as a chemoresistant disease. Recently, it was found that 14-3-3sigma expression increases as prostate tumor progresses, and that 14-3-3sigma contributes significantly to drug resistance in breast cancers. We, thus, hypothesized that advanced and ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0393

    authors: Han B,Xie H,Chen Q,Zhang JT

    更新日期:2006-04-01 00:00:00

  • Inhibition of Nucleotide Synthesis Targets Brain Tumor Stem Cells in a Subset of Glioblastoma.

    abstract::Inhibition of both the de novo (DNP) and salvage (NSP) pathways of nucleoside synthesis has been demonstrated to impair leukemia cells. We endeavored to determine whether this approach would be efficacious in glioblastoma. To diminish nucleoside biosynthesis, we utilized compound DI-39, which selectively targets NSP, ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0982

    authors: Laks DR,Ta L,Crisman TJ,Gao F,Coppola G,Radu CG,Nathanson DA,Kornblum HI

    更新日期:2016-06-01 00:00:00

  • A New Class of Bifunctional Major Histocompatibility Class I Antibody Fusion Molecules to Redirect CD8 T Cells.

    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

    authors: Schmittnaegel M,Hoffmann E,Imhof-Jung S,Fischer C,Drabner G,Georges G,Klein C,Knoetgen H

    更新日期:2016-09-01 00:00:00

  • Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors.

    abstract::ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically tho...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-0991

    authors: Xia W,Liu Z,Zong R,Liu L,Zhao S,Bacus SS,Mao Y,He J,Wulfkuhle JD,Petricoin EF 3rd,Osada T,Yang XY,Hartman ZC,Clay TM,Blackwell KL,Lyerly HK,Spector NL

    更新日期:2011-08-01 00:00:00

  • Targeted delivery to PEPT1-overexpressing cells: acidic, basic, and secondary floxuridine amino acid ester prodrugs.

    abstract::Floxuridine is a clinically proven anticancer agent in the treatment of metastatic colon carcinomas and hepatic metastases. However, prodrug strategies may be necessary to improve its physiochemical properties and selectivity and to reduce undesirable toxicity effects. Previous studies with amino acid ester prodrugs o...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-04-0290

    authors: Landowski CP,Vig BS,Song X,Amidon GL

    更新日期:2005-04-01 00:00:00

  • In vitro cytotoxicity of carcinoma cells with 111In-labeled antibodies to HER-2.

    abstract::Antibodies conjugated to radionuclides emitting low-energy electrons, which include Auger electrons and some conversion electrons, were recently shown to efficiently kill cells bearing a high density of the antigen recognized. The primary purpose of this study was to determine if such killing could be obtained with an...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-04-0340

    authors: Michel RB,Andrews PM,Castillo ME,Mattes MJ

    更新日期:2005-06-01 00:00:00

  • In vitro and in vivo responses of advanced prostate tumors to PSMA ADC, an auristatin-conjugated antibody to prostate-specific membrane antigen.

    abstract::Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for therapy. PSMA ADC is an antibody-drug conjugate (ADC) that consists of a fully human anti-PSMA monoclonal antibody conjugated to monomethylauristatin E through a valin...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-11-0191

    authors: Wang X,Ma D,Olson WC,Heston WD

    更新日期:2011-09-01 00:00:00

  • TAS-121, A Selective Mutant EGFR Inhibitor, Shows Activity Against Tumors Expressing Various EGFR Mutations Including T790M and Uncommon Mutations G719X.

    abstract::TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T7...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-0645

    authors: Ito K,Nishio M,Kato M,Murakami H,Aoyagi Y,Ohe Y,Okayama T,Hashimoto A,Ohsawa H,Tanaka G,Nonoshita K,Ito S,Matsuo K,Miyadera K

    更新日期:2019-05-01 00:00:00

  • A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway.

    abstract::Many genes, with products involved in the protection of cells against carcinogens, oxidants, and other toxic chemicals, are under the transcriptional control of a simple DNA regulatory element [i.e., the antioxidant response element (ARE)]. One or more functional AREs have been confirmed or are believed to exist in th...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:

    authors: Zhang Y,Gordon GB

    更新日期:2004-07-01 00:00:00

  • Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab.

    abstract::Cetuximab, an antibody against the EGFR, has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer, and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do i...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-16-0012

    authors: Iida M,Bahrar H,Brand TM,Pearson HE,Coan JP,Orbuch RA,Flanigan BG,Swick AD,Prabakaran PJ,Lantto J,Horak ID,Kragh M,Salgia R,Kimple RJ,Wheeler DL

    更新日期:2016-09-01 00:00:00

  • Therapeutic targeting of angiogenesis with a recombinant CTT peptide-endostatin mimic-kringle 5 protein.

    abstract::Angiogenesis is required for tumor growth and metastasis, and targeting angiogenesis is a novel anticancer strategy. However, cancer development is a complex multistep process, and single antiangiogenic agents have limited therapeutic efficacy. Here, we report a triple fusion protein, namely CTT peptide-endostatin mim...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0266

    authors: Wang H,Yang Z,Gu J

    更新日期:2014-11-01 00:00:00

  • Targeting the PI3K/AKT Pathway Overcomes Enzalutamide Resistance by Inhibiting Induction of the Glucocorticoid Receptor.

    abstract::The PI3K-AKT pathway has pleiotropic effects and its inhibition has long been of interest in the management of prostate cancer, where a compensatory increase in PI3K signaling has been reported following androgen receptor (AR) blockade. Prostate cancer cells can also bypass AR blockade through induction of other hormo...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-19-0936

    authors: Adelaiye-Ogala R,Gryder BE,Nguyen YTM,Alilin AN,Grayson AR,Bajwa W,Jansson KH,Beshiri ML,Agarwal S,Rodriguez-Nieves JA,Capaldo B,Kelly K,VanderWeele DJ

    更新日期:2020-07-01 00:00:00

  • Combined inhibition of HER1/EGFR and RAC1 results in a synergistic antiproliferative effect on established and primary cultured human glioblastoma cells.

    abstract::Glioblastoma is the most frequent brain tumor of glial origin in adults. With the best available standard-of-care, patients with this disease have a life expectancy of only approximately 15 months after diagnosis. Because the EGF receptor (HER1/EGFR) is one of the most commonly dysregulated oncogenes in glioblastoma, ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0052

    authors: Karpel-Massler G,Westhoff MA,Zhou S,Nonnenmacher L,Dwucet A,Kast RE,Bachem MG,Wirtz CR,Debatin KM,Halatsch ME

    更新日期:2013-09-01 00:00:00

  • 2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N-Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3β Activation.

    abstract::Interference with endothelial cell metabolism is a promising, yet unexploited strategy for angiogenesis inhibition. We reported that the glucose analogue 2-deoxy-D-glucose (2-DG) inhibits angiogenesis at significantly lower concentrations than those required for tumor cytotoxicity. Here, we found that hypersensitivity...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0315

    authors: Kovács K,Decatur C,Toro M,Pham DG,Liu H,Jing Y,Murray TG,Lampidis TJ,Merchan JR

    更新日期:2016-02-01 00:00:00

  • Cdc25A-inhibitory properties and antineoplastic activity of bisperoxovanadium analogues.

    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:

    authors: Scrivens PJ,Alaoui-Jamali MA,Giannini G,Wang T,Loignon M,Batist G,Sandor VA

    更新日期:2003-10-01 00:00:00

  • Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation.

    abstract::The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Although irreversible EGFR TKIs, such as afatinib or dacomitinib, have been introduced to overcome the acquired resistanc...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-0311

    authors: Kim SM,Kwon OJ,Hong YK,Kim JH,Solca F,Ha SJ,Soo RA,Christensen JG,Lee JH,Cho BC

    更新日期:2012-10-01 00:00:00

  • D,L-Sulforaphane causes transcriptional repression of androgen receptor in human prostate cancer cells.

    abstract::D,L-Sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L-isomer, inhibits the growth of human prostate cancer cells in culture and in vivo and retards cancer development in a transgenic mouse model of prostate cancer. We now show that SFN treatment causes transcriptional repression of androgen r...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0104

    authors: Kim SH,Singh SV

    更新日期:2009-07-01 00:00:00

  • Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma.

    abstract::Multiple myeloma remains incurable and the majority of patients die within 5 years of diagnosis. Reolysin, the infusible form of human reovirus (RV), is a novel viral oncolytic therapy associated with antitumor activity likely resulting from direct oncolysis and a virus-mediated antitumor immune response. Results from...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0240-T

    authors: Stiff A,Caserta E,Sborov DW,Nuovo GJ,Mo X,Schlotter SY,Canella A,Smith E,Badway J,Old M,Jaime-Ramirez AC,Yan P,Benson DM,Byrd JC,Baiocchi R,Kaur B,Hofmeister CC,Pichiorri F

    更新日期:2016-05-01 00:00:00

  • Mechanism of drug efficacy within the EGF receptor revealed by microsecond molecular dynamics simulation.

    abstract::The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine k...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-0644-T

    authors: Wan S,Wright DW,Coveney PV

    更新日期:2012-11-01 00:00:00

  • The G-rich promoter and G-rich coding sequence of basic fibroblast growth factor are the targets of thalidomide in glioma.

    abstract::Thalidomide is considered to be a potent antiangiogenic and immunomodulatory drug for cancer therapy. Earlier clinical studies have found that patients responding to this drug often had high plasma levels of basic fibroblast growth factor (bFGF). This cytokine is a proangiogenic factor overexpressed in many tumors and...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-2398

    authors: Mei SC,Wu RT

    更新日期:2008-08-01 00:00:00

  • Recombinant adeno-associated virus encoding Epstein-Barr virus latent membrane proteins fused with heat shock protein as a potential vaccine for nasopharyngeal carcinoma.

    abstract::Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and EBV is the most important pathogenesis. In this study, we explore the potential that a recombinant adeno-associated virus (rAAV) carrying a fusing gene containing heat shock protein as an adjuvant, EBV latent membrane proteins (LMP1 and LMP2) CTL ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-1176

    authors: Pan J,Zhang Q,Zhou J,Ma D,Xiao X,Wang DW

    更新日期:2009-09-01 00:00:00

  • First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer.

    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

    authors: Capasso A,Bagby SM,Dailey KL,Currimjee N,Yacob BW,Ionkina A,Frank JG,Kim DJ,George C,Lee YB,Benaim E,Gittleman B,Hartman SJ,Tan AC,Kim J,Pitts TM,Eckhardt SG,Tentler JJ,Diamond JR

    更新日期:2019-11-01 00:00:00

  • MAP-ing glioma invasion: mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival.

    abstract::Although astrocytic brain tumors do not metastasize systemically, during tumorigenesis glioma cells adopt an invasive phenotype that is poorly targeted by conventional therapies; hence, glioma patients die of recurrence from the locally invasive tumor population. Our work is aimed at identifying and validating novel t...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0711

    authors: Demuth T,Reavie LB,Rennert JL,Nakada M,Nakada S,Hoelzinger DB,Beaudry CE,Henrichs AN,Anderson EM,Berens ME

    更新日期:2007-04-01 00:00:00

  • A new nonestrogenic steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type I blocks the estrogen-dependent breast cancer tumor growth induced by estrone.

    abstract::17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) converts estrone (E1) into estradiol (E2) and is expressed in many steroidogenic tissues and breast cancer cell lines. Because the potent estrogen E2 stimulates the growth and development of hormone-dependent diseases, inhibition of the final step of E2 synthesis is c...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-0299

    authors: Ayan D,Maltais R,Roy J,Poirier D

    更新日期:2012-10-01 00:00:00