Off-target lapatinib activity sensitizes colon cancer cells through TRAIL death receptor up-regulation.

Abstract:

:Lapatinib, a dual HER2/EGFR (human epidermal growth factor receptor 2/epidermal growth factor receptor) inhibitor, is a recently approved targeted therapy for metastatic breast cancer. Because lapatinib enhances the efficacy of the chemotherapeutic agent capecitabine in breast cancer patients, we tested whether lapatinib also enhances the activity of anticancer agents in colorectal cancer. We found that lapatinib improved the proapoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab. Tumors from mice treated with a combination of lapatinib and TRAIL exhibited more immunostaining for cleaved caspase-8, a marker of the extrinsic cell death pathway, than did tumors from mice treated with lapatinib or TRAIL alone. Furthermore, combination therapy suppressed tumor growth more effectively than either agent alone. Lapatinib up-regulated the proapoptotic TRAIL death receptors DR4 and DR5, leading to more efficient induction of apoptosis in the presence of TRAIL receptor agonists. This activity of lapatinib was independent of EGFR and HER2. The off-target induction of DR5 by lapatinib resulted from activation of the c-Jun amino-terminal kinase (JNK)/c-Jun signaling axis. This activity of lapatinib on TRAIL death receptor expression and signaling may confer therapeutic benefit when increased doses of lapatinib are used in combination with TRAIL receptor-activating agents.

journal_name

Sci Transl Med

authors

Dolloff NG,Mayes PA,Hart LS,Dicker DT,Humphreys R,El-Deiry WS

doi

10.1126/scitranslmed.3001384

subject

Has Abstract

pub_date

2011-06-08 00:00:00

pages

86ra50

issue

86

eissn

1946-6234

issn

1946-6242

pii

3/86/86ra50

journal_volume

3

pub_type

杂志文章
  • Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection.

    abstract::Disease-free infection in HIV-infected adults is associated with human leukocyte antigen-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we i...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aag1048

    authors: Muenchhoff M,Adland E,Karimanzira O,Crowther C,Pace M,Csala A,Leitman E,Moonsamy A,McGregor C,Hurst J,Groll A,Mori M,Sinmyee S,Thobakgale C,Tudor-Williams G,Prendergast AJ,Kloverpris H,Roider J,Leslie A,Shingadia D

    更新日期:2016-09-28 00:00:00

  • Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.

    abstract::Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8(+) T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejecte...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3006504

    authors: Spranger S,Spaapen RM,Zha Y,Williams J,Meng Y,Ha TT,Gajewski TF

    更新日期:2013-08-28 00:00:00

  • Aptamers against mouse and human tumor-infiltrating myeloid cells as reagents for targeted chemotherapy.

    abstract::Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells in...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aav9760

    authors: De La Fuente A,Zilio S,Caroli J,Van Simaeys D,Mazza EMC,Ince TA,Bronte V,Bicciato S,Weed DT,Serafini P

    更新日期:2020-06-17 00:00:00

  • A light-reflecting balloon catheter for atraumatic tissue defect repair.

    abstract::A congenital or iatrogenic tissue defect often requires closure by open surgery or metallic components that can erode tissue. Biodegradable, hydrophobic light-activated adhesives represent an attractive alternative to sutures, but lack a specifically designed minimally invasive delivery tool, which limits their clinic...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaa2406

    authors: Roche ET,Fabozzo A,Lee Y,Polygerinos P,Friehs I,Schuster L,Whyte W,Casar Berazaluce AM,Bueno A,Lang N,Pereira MJ,Feins E,Wasserman S,O'Cearbhaill ED,Vasilyev NV,Mooney DJ,Karp JM,Del Nido PJ,Walsh CJ

    更新日期:2015-09-23 00:00:00

  • PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma.

    abstract::Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chro...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aay0152

    authors: Jiang TY,Pan YF,Wan ZH,Lin YK,Zhu B,Yuan ZG,Ma YH,Shi YY,Zeng TM,Dong LW,Tan YX,Wang HY

    更新日期:2020-09-23 00:00:00

  • Tissue-specific regulation of p53 by PKM2 is redox dependent and provides a therapeutic target for anthracycline-induced cardiotoxicity.

    abstract::Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Althoug...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aau8866

    authors: Saleme B,Gurtu V,Zhang Y,Kinnaird A,Boukouris AE,Gopal K,Ussher JR,Sutendra G

    更新日期:2019-02-06 00:00:00

  • Temporal dynamics of the human vaginal microbiota.

    abstract::Elucidating the factors that impinge on the stability of bacterial communities in the vagina may help in predicting the risk of diseases that affect women's health. Here, we describe the temporal dynamics of the composition of vaginal bacterial communities in 32 reproductive-age women over a 16-week period. The analys...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3003605

    authors: Gajer P,Brotman RM,Bai G,Sakamoto J,Schütte UM,Zhong X,Koenig SS,Fu L,Ma ZS,Zhou X,Abdo Z,Forney LJ,Ravel J

    更新日期:2012-05-02 00:00:00

  • Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD).

    abstract::Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)-related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3008481

    authors: Fink SP,Yamauchi M,Nishihara R,Jung S,Kuchiba A,Wu K,Cho E,Giovannucci E,Fuchs CS,Ogino S,Markowitz SD,Chan AT

    更新日期:2014-04-23 00:00:00

  • Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination.

    abstract::The four dengue virus serotypes (DENV1 to DENV4) are mosquito-borne flaviviruses that cause up to ~100 million cases of dengue annually worldwide. Severe disease is thought to result from immunopathogenic processes involving serotype cross-reactive antibodies and T cells that together induce vasoactive cytokines, caus...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaa3787

    authors: Beatty PR,Puerta-Guardo H,Killingbeck SS,Glasner DR,Hopkins K,Harris E

    更新日期:2015-09-09 00:00:00

  • Quantifying prion disease penetrance using large population control cohorts.

    abstract::More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aad5169

    authors: Minikel EV,Vallabh SM,Lek M,Estrada K,Samocha KE,Sathirapongsasuti JF,McLean CY,Tung JY,Yu LP,Gambetti P,Blevins J,Zhang S,Cohen Y,Chen W,Yamada M,Hamaguchi T,Sanjo N,Mizusawa H,Nakamura Y,Kitamoto T,Collins SJ,

    更新日期:2016-01-20 00:00:00

  • Comment on "A small-molecule antivirulence agent for treating Clostridium difficile infection".

    abstract::New insights into the mechanism of action of ebselen, a small-molecule antivirulence agent that reduces disease pathology in a mouse model of Clostridium difficile infection, suggest a different molecular target may be responsible for its efficacy. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aad8926

    authors: Beilhartz GL,Tam J,Zhang Z,Melnyk RA

    更新日期:2016-12-21 00:00:00

  • Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment.

    abstract::Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combinat...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aav7816

    authors: Zemek RM,De Jong E,Chin WL,Schuster IS,Fear VS,Casey TH,Forbes C,Dart SJ,Leslie C,Zaitouny A,Small M,Boon L,Forrest ARR,Muiri DO,Degli-Esposti MA,Millward MJ,Nowak AK,Lassmann T,Bosco A,Lake RA,Lesterhuis WJ

    更新日期:2019-07-17 00:00:00

  • Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma.

    abstract::The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3003016

    authors: Munson JM,Fried L,Rowson SA,Bonner MY,Karumbaiah L,Diaz B,Courtneidge SA,Knaus UG,Brat DJ,Arbiser JL,Bellamkonda RV

    更新日期:2012-03-28 00:00:00

  • Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity.

    abstract::Obesity increases the risk of adverse outcomes during acute critical illnesses such as burns, severe trauma, and acute pancreatitis. Although individuals with more body fat and higher serum cytokines and lipase are more likely to experience problems, the roles that these characteristics play are not clear. We used sev...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3002573

    authors: Navina S,Acharya C,DeLany JP,Orlichenko LS,Baty CJ,Shiva SS,Durgampudi C,Karlsson JM,Lee K,Bae KT,Furlan A,Behari J,Liu S,McHale T,Nichols L,Papachristou GI,Yadav D,Singh VP

    更新日期:2011-11-02 00:00:00

  • Repurposed drug to the rescue of snakebite victims.

    abstract::Preclinical data suggest the possibility of repurposing a drug for early intervention in envenoming by snake venom rich in metalloproteinases (Albulescu et al., this issue). ...

    journal_title:Science translational medicine

    pub_type: 杂志文章,评审

    doi:10.1126/scitranslmed.abb6700

    authors: Koh CY,Bendre R,Kini RM

    更新日期:2020-05-06 00:00:00

  • Circadian actin dynamics drive rhythmic fibroblast mobilization during wound healing.

    abstract::Fibroblasts are primary cellular protagonists of wound healing. They also exhibit circadian timekeeping, which imparts an approximately 24-hour rhythm to their biological function. We interrogated the functional consequences of the cell-autonomous clockwork in fibroblasts using a proteome-wide screen for rhythmically ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aal2774

    authors: Hoyle NP,Seinkmane E,Putker M,Feeney KA,Krogager TP,Chesham JE,Bray LK,Thomas JM,Dunn K,Blaikley J,O'Neill JS

    更新日期:2017-11-08 00:00:00

  • Splicing-directed therapy in a new mouse model of human accelerated aging.

    abstract::Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent dev...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3002847

    authors: Osorio FG,Navarro CL,Cadiñanos J,López-Mejía IC,Quirós PM,Bartoli C,Rivera J,Tazi J,Guzmán G,Varela I,Depetris D,de Carlos F,Cobo J,Andrés V,De Sandre-Giovannoli A,Freije JM,Lévy N,López-Otín C

    更新日期:2011-10-26 00:00:00

  • Working stiff: how obesity boosts cancer risk.

    abstract::Obesity promotes breast cancer by enhancing the stiffness of breast adipose tissue through changes in the extracellular matrix (Seo et al., this issue). ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aac9446

    authors: Arendt LM,Kuperwasser C

    更新日期:2015-08-19 00:00:00

  • The gracefully aging immune system.

    abstract::Prolonged life expectancy in the 20th century has been one of humankind's greatest triumphs. However, the substantial increase in the human life span has ushered in a new concern: healthy aging. Because infectious diseases prominently contribute to morbidity in the particularly vulnerable elderly population, strategie...

    journal_title:Science translational medicine

    pub_type: 杂志文章,评审

    doi:10.1126/scitranslmed.3005624

    authors: Boraschi D,Aguado MT,Dutel C,Goronzy J,Louis J,Grubeck-Loebenstein B,Rappuoli R,Del Giudice G

    更新日期:2013-05-15 00:00:00

  • Fresh approaches to anti-infective therapies.

    abstract::If discovery of new antibiotics continues to falter while resistance to drugs in clinical use continues to spread, society's medicine chest will soon lack effective treatments for many infections. Heritable antibiotic resistance emerges in bacteria from nonheritable resistance, also called phenotypic tolerance. This w...

    journal_title:Science translational medicine

    pub_type: 杂志文章,评审

    doi:10.1126/scitranslmed.3003081

    authors: Nathan C

    更新日期:2012-06-27 00:00:00

  • Development of personalized tumor biomarkers using massively parallel sequencing.

    abstract::Clinical management of human cancer is dependent on the accurate monitoring of residual and recurrent tumors. The evaluation of patient-specific translocations in leukemias and lymphomas has revolutionized diagnostics for these diseases. We have developed a method, called personalized analysis of rearranged ends (PARE...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000702

    authors: Leary RJ,Kinde I,Diehl F,Schmidt K,Clouser C,Duncan C,Antipova A,Lee C,McKernan K,De La Vega FM,Kinzler KW,Vogelstein B,Diaz LA Jr,Velculescu VE

    更新日期:2010-02-24 00:00:00

  • A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence.

    abstract::Buprenorphine, a synthetic opioid that acts at both μ and κ opioid receptors, can decrease cocaine use in individuals with opioid addiction. However, the potent agonist action of buprenorphine at μ opioid receptors raises its potential for creating opioid dependence in non-opioid-dependent cocaine abusers. Here, we te...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3003948

    authors: Wee S,Vendruscolo LF,Misra KK,Schlosburg JE,Koob GF

    更新日期:2012-08-08 00:00:00

  • Brief suppression of Abcc8 prevents autodestruction of spinal cord after trauma.

    abstract::Spinal cord injury (SCI) is typically complicated by progressive hemorrhagic necrosis, an autodestructive process of secondary injury characterized by progressive enlargement of a hemorrhagic contusion during the first several hours after trauma. We assessed the role of Abcc8, which encodes sulfonylurea receptor 1 (SU...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000522

    authors: Simard JM,Woo SK,Norenberg MD,Tosun C,Chen Z,Ivanova S,Tsymbalyuk O,Bryan J,Landsman D,Gerzanich V

    更新日期:2010-04-21 00:00:00

  • Continuous intravesical lidocaine treatment for interstitial cystitis/bladder pain syndrome: safety and efficacy of a new drug delivery device.

    abstract::Limited treatment options exist for patients who suffer from a painful bladder condition known as interstitial cystitis/bladder pain syndrome (IC/BPS). Whether given systemically (orally) or by short-duration (1 to 2 hours) exposure via intravesical instillation, therapeutic agents have exhibited poor efficacy because...

    journal_title:Science translational medicine

    pub_type: 杂志文章,随机对照试验

    doi:10.1126/scitranslmed.3003804

    authors: Nickel JC,Jain P,Shore N,Anderson J,Giesing D,Lee H,Kim G,Daniel K,White S,Larrivee-Elkins C,Lekstrom-Himes J,Cima M

    更新日期:2012-07-18 00:00:00

  • Design of vaccine efficacy trials during public health emergencies.

    abstract::Public health emergencies, such as an Ebola disease outbreak, provide a complex and challenging environment for the evaluation of candidate vaccines. Here, we outline the need for flexible and responsive vaccine trial designs to be used in public health emergencies, and we summarize recommendations for their use in th...

    journal_title:Science translational medicine

    pub_type: 杂志文章,评审

    doi:10.1126/scitranslmed.aat0360

    authors: Dean NE,Gsell PS,Brookmeyer R,De Gruttola V,Donnelly CA,Halloran ME,Jasseh M,Nason M,Riveros X,Watson CH,Henao-Restrepo AM,Longini IM

    更新日期:2019-07-03 00:00:00

  • Long synthetic peptides for the production of vaccines and drugs: a technological platform coming of age.

    abstract::Long synthetic peptides (LSPs) have a variety of important clinical uses as synthetic vaccines and drugs. Techniques for peptide synthesis were revolutionized in the 1960s and 1980s, after which efficient techniques for purification and characterization of the product were developed. These improved techniques allowed ...

    journal_title:Science translational medicine

    pub_type: 杂志文章,评审

    doi:10.1126/scitranslmed.3001387

    authors: Corradin G,Kajava AV,Verdini A

    更新日期:2010-09-22 00:00:00

  • Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus.

    abstract::Vaccines against influenza viruses with pandemic potential, including H5N1, are under development. Because of a lack of preexisting immunity to these viruses, adjuvants (immune potentiators or enhancers) are needed to improve immune responses, to conserve scarce vaccine, and for cross-protection against strains that h...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000624

    authors: Khurana S,Chearwae W,Castellino F,Manischewitz J,King LR,Honorkiewicz A,Rock MT,Edwards KM,Del Giudice G,Rappuoli R,Golding H

    更新日期:2010-01-20 00:00:00

  • A Mucin 16 bispecific T cell-engaging antibody for the treatment of ovarian cancer.

    abstract::Advanced ovarian cancer is frequently treated with combination chemotherapy, but high recurrence rates show the need for therapies that can produce durable responses and extend overall survival. Bispecific antibodies that interact with tumor antigens on cancer cells and activating receptors on immune cells offer an in...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aau7534

    authors: Crawford A,Haber L,Kelly MP,Vazzana K,Canova L,Ram P,Pawashe A,Finney J,Jalal S,Chiu D,Colleton CA,Garnova E,Makonnen S,Hickey C,Krueger P,DelFino F,Potocky T,Kuhnert J,Godin S,Retter MW,Duramad P,MacDonald D,

    更新日期:2019-06-19 00:00:00

  • Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome.

    abstract::Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aat4822

    authors: Habashi JP,MacFarlane EG,Bagirzadeh R,Bowen C,Huso N,Chen Y,Bedja D,Creamer TJ,Rykiel G,Manning M,Huso D,Dietz HC

    更新日期:2019-05-01 00:00:00

  • Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases.

    abstract::Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K-nul...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaw6143

    authors: Zhu L,Tang Y,Li XY,Keller ET,Yang J,Cho JS,Feinberg TY,Weiss SJ

    更新日期:2020-02-05 00:00:00