EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma.

Abstract:

:The pediatric solid tumor neuroblastoma (NB) often depends on the anti-apoptotic protein, Mcl(-)1, for survival through Mcl(-)1 sequestration of pro-apoptotic Bim. High affinity Mcl(-)1 inhibitors currently do not exist such that novel methods to inhibit Mcl(-)1 clinically are in high demand. Receptor tyrosine kinases (RTK) regulate Mcl(-)1 in many cancers and play a role in NB survival, yet how they regulate Bcl(-)2 family interactions in NB is unknown. We found that NB cell lines derived to resist the Bcl(-)2/-xl/-w antagonist, ABT-737, acquire a dependence on Mcl(-)1 and show increased expression and activation of the RTK, EGFR. Mcl(-)1 dependent NB cell lines derived at diagnosis and from the same tumor following relapse also have increased EGFR expression compared to those dependent on Bcl(-)2. Inhibition of EGFR by shRNA or erlotinib in Mcl(-)1 dependent NBs disrupts Bim binding to Mcl(-)1 and enhances its affinity for Bcl(-)2, restoring sensitivity to ABT-737 as well as cytotoxics in vitro. Mechanistically treatment of NBs with small molecule inhibitors of EGFR (erlotinib, cetuximab) and ERK (U0126) increases Noxa expression and dephosphorylates Bim to promote Bim binding to Bcl(-)2. Thus, EGFR regulates Mcl(-)1 dependence in high-risk NB via ERK-mediated phosphorylation of Bim such that EGFR/ERK inhibition renders Mcl(-)1 dependent tumors now reliant on Bcl(-)2. Clinically, EGFR inhibitors are ineffective as single agent compounds in patients with recurrent NB, likely due to this transferred survival dependence to Bcl(-)2. Likewise, EGFR or ERK inhibitors warrant further testing in combination with Bcl(-)2 antagonists in vivo as a novel future combination to overcome therapy resistance in the clinic.

journal_name

Cancer Biol Ther

journal_title

Cancer biology & therapy

authors

Nalluri S,Peirce SK,Tanos R,Abdella HA,Karmali D,Hogarty MD,Goldsmith KC

doi

10.1080/15384047.2014.1002333

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

276-86

issue

2

eissn

1538-4047

issn

1555-8576

journal_volume

16

pub_type

杂志文章
  • Type B lactic acidosis, an uncommon paraneoplastic syndrome.

    abstract::A 67-year-old male presented with anasarca and persistent non-pruritic rash of lower extremities. Physical examination was positive for subcutaneous edema with a non-blanching rash of abdomen and lower extremities. Labs showed leukocytosis, lymphocytosis, anemia and thrombocytopenia. He also had acute kidney injury an...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2017.1394550

    authors: Wahab A,Kesari K,J Smith S,Liu Y,Barta SK

    更新日期:2018-02-01 00:00:00

  • IDO inhibits T-cell function through suppressing Vav1 expression and activation.

    abstract:PURPOSE:Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolic enzyme, plays an important role in immune escape through suppressing T-cell function. Since Vav1 signaling pathway regulates T cell homeostasis, this study was designed to test the hypothesis that IDO induces T-cell immunosuppression through inhibiting V...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.8.14.8882

    authors: Li R,Wei F,Yu J,Li H,Ren X,Hao X

    更新日期:2009-07-01 00:00:00

  • Exploiting defects in homologous recombination repair for metastatic, castration-resistant prostate cancer.

    abstract::The PROfound trial highlights that there is a benefit in testing genes involved in homologous recombination (HR) and forms the rationale for testing in all patients with metastatic, castration-resistant prostate cancer (mCRPC). This trial also demostrates that olaparib improves progression free survival (PFS), objecti...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2020.1809913

    authors: Chau V,Madan RA,Figg WD

    更新日期:2020-10-02 00:00:00

  • Negative regulation of the oncogenic transcription factor FoxM1 by thiazolidinediones and mithramycin.

    abstract::The Forkhead Box transcription factor FoxM1 regulates expression of genes that promote cell cycle progression, and it plays essential roles in the development of liver, lung, prostate and colorectal tumors. Thiazolidinediones (TZDs) activate the peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activa...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.9.12.11710

    authors: Petrovic V,Costa RH,Lau LF,Raychaudhuri P,Tyner AL

    更新日期:2010-06-15 00:00:00

  • Kmt2a cooperates with menin to suppress tumorigenesis in mouse pancreatic islets.

    abstract::The reported incidence of pancreatic neuroendocrine tumors (PanNETs) has increased, due in large part to improvements in detection and awareness. However, therapeutic options are limited and a critical need exists for understanding a more thorough characterization of the molecular pathology underlying this disease. Th...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2016.1250986

    authors: Lin W,Francis JM,Li H,Gao X,Pedamallu CS,Ernst P,Meyerson M

    更新日期:2016-12-01 00:00:00

  • Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study.

    abstract::The surprising results published by FIRE-3 revealed that the overall survival (OS) of RAS wild-type metastatic colorectal cancer (mCRC) patients treated with Cetuximab(Cmab) and FOLFIRI combination was prolonged to 33.1 months. The substantial increase in testing and treatment costs, however, impose a considerable hea...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2015.1095398

    authors: Wen F,Yang Y,Zhang P,Zhang J,Zhou J,Tang R,Chen H,Zheng H,Fu P,Li Q

    更新日期:2015-01-01 00:00:00

  • Adenovirus-mediated Ink4a/ARF gene transfer significantly suppressed the growth of pancreatic carcinoma cells.

    abstract:OBJECTIVES:To determine the effects of adenovirus-mediated transfer of p14(ARF) and p16(INK4a) on growth and apoptosis of human pancreatic carcinoma cell lines. RESULTS:Pancreatic carcinoma cell lines, PC-7, PANC-1 and MIA PaCa-2 (p14(ARF)-/- and p16(INK4a)-/-), were used. PC-7 (p53 wt) and MIA PaCa-2 (p53 mt) cells i...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.4.12.2183

    authors: Chen F,Li Y,Lu Z,Gao J,Chen J

    更新日期:2005-12-01 00:00:00

  • Peroxisome proliferator-activated receptor gamma in bladder cancer: a promising therapeutic target.

    abstract::Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated intracellular transcription factors, members of the nuclear hormone receptor superfamily. The PPAR subfamily consist of three subtypes encoded by distinct genes denoted PPARalpha, PPARbeta/delta, and PPARgamma. The peroxisome proliferator-activat...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章,评审

    doi:10.4161/cbt.8.7.7853

    authors: Mansure JJ,Nassim R,Kassouf W

    更新日期:2009-04-01 00:00:00

  • Increased gene copy number of the transcription factor E2F1 in malignant melanoma.

    abstract::Translocations and unique chromosome break points in melanoma will aid in the identification of the genes that are important in the neoplastic process. We have previously shown a unique translocation in malignant melanoma cells der(12)t(12;20). The transcription factor E2F1 maps to 20q11. Increased expression of E2F h...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.5.4.2512

    authors: Nelson MA,Reynolds SH,Rao UN,Goulet AC,Feng Y,Beas A,Honchak B,Averill J,Lowry DT,Senft JR,Jefferson AM,Johnson RC,Sargent LM

    更新日期:2006-04-01 00:00:00

  • Polymorphisms of SPINK1 N34S and CFTR in patients with sporadic and familial pancreatic cancer.

    abstract::Long standing chronic pancreatitis is a risk factor for developing pancreatic cancer. Inheritance of polymorphisms in SPINK1 and CFTR are associated with an increased risk of developing pancreatitis. The aim of this study was to determine if patients who carry polymorphisms in SPINK1 and CFTR are at increased risk of ...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:

    authors: Matsubayashi H,Fukushima N,Sato N,Brune K,Canto M,Yeo CJ,Hruban RH,Kern SE,Goggins M

    更新日期:2003-11-01 00:00:00

  • Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1.

    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

    authors: Huang XZ,Wang J,Huang C,Chen YY,Shi GY,Hu QS,Yi J

    更新日期:2008-03-01 00:00:00

  • No association between XRCC1 polymorphisms and survival in non-small-cell lung cancer patients treated with platinum-based chemotherapy.

    abstract:PURPOSE:genetic polymorphisms in DNA repair genes are thought to represent important determinants of platinum drug efficacy. The current study investigated whether single nucleotide polymorphisms (SNPs) in the X-ray repair cross complementing protein 1 (XRCC1) gene are associated with survival in non-small-cell lung ca...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.10.9.13238

    authors: Yuan P,Liu L,Wu C,Zhong R,Yu D,Wu J,Xu Y,Nie S,Miao X,Sun Y,Xu B,Lin D

    更新日期:2010-11-01 00:00:00

  • Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubicin.

    abstract::Exosomes released from cancer cells support metastasis and growth of recipient cells and increase their resistance to chemotherapy. Therapeutic targeting of exosomes is a promising area in cancer research. Our aim is to test the effect of the mast cell stabilizer ketotifen on exosomes release from cancer cells and how...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2017.1394544

    authors: Khan FM,Saleh E,Alawadhi H,Harati R,Zimmermann WH,El-Awady R

    更新日期:2018-01-02 00:00:00

  • A proposed clinical test for monitoring fluoropyrimidine therapy: detection and stability of thymidylate synthase ternary complexes.

    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

    authors: Brody JR,Gallmeier E,Yoshimura K,Hucl T,Kulesza P,Canto MI,Hruban RH,Schulick RD,Kern SE

    更新日期:2006-08-01 00:00:00

  • The role of apoptosis in cancer cell survival and therapeutic outcome.

    abstract::A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and therapeutic outcome. Even though apoptosis is thought to play a major role in anticancer therapy, the clinical relevance of induction of apoptosis remains uncertain, particularly in solid tumors....

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章,评审

    doi:10.4161/cbt.5.11.3456

    authors: Kim R,Emi M,Tanabe K

    更新日期:2006-11-01 00:00:00

  • Combined targeting of EGFR and HER2 against prostate cancer stem cells.

    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

    authors: Rossini A,Giussani M,Ripamonti F,Aiello P,Regondi V,Balsari A,Triulzi T,Tagliabue E

    更新日期:2020-05-03 00:00:00

  • Inhibiting gastric cancer-associated angiogenesis by CIAPIN1 siRNA.

    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

    authors: Yan K,He LJ,Cheng W,Ji ZZ,Zhao BX,Hui XL,Cao SS,Chen B,He L,Liang SH,Miao Y

    更新日期:2009-06-01 00:00:00

  • Epigenetic modulation of FBW7/Mcl-1 pathway for lung cancer therapy.

    abstract::Methylation induces epigenetic silencing of tumor suppressor genes in human lung cancer. Inhibition of DNA methyltransferases by decitabine (DAC) can demethylate and activate epigenetically silenced tumor suppressor genes. Epigenetic therapy using DAC should be an attractive strategy for lung cancer therapy. FBW7 is a...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2020.1856756

    authors: Kim MJ,Chen G,Sica GL,Deng X

    更新日期:2021-01-02 00:00:00

  • Inhibition of Hsp27 and Hsp40 potentiates 5-fluorouracil and carboplatin mediated cell killing in hepatoma cells.

    abstract::Heat shock proteins (Hsps) modulate several cellular functions and are ubiquitously present in cell. Here, we investigated alterations in the expression of Hsps and explored functional consequences of the same. Moreover, effect of quercetin (Qctn), an inhibitor of Hsps, on chemotherapeutic drugs treatment in hepatoma ...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.8.22.9687

    authors: Sharma A,Upadhyay AK,Bhat MK

    更新日期:2009-11-01 00:00:00

  • Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib.

    abstract::Medulloblastoma is an aggressive primitive neuroectodermal tumor of the cerebellum that is rare in adults. Medulloblastomas fall into 4 prognostically significant molecular subgroups that are best defined by experimental gene expression profiles: the WNT pathway, sonic hedgehog (SHH) pathway, and subgroups 3 and 4 (no...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2016.1220453

    authors: Lou E,Schomaker M,Wilson JD,Ahrens M,Dolan M,Nelson AC

    更新日期:2016-10-02 00:00:00

  • Ras family signaling: therapeutic targeting.

    abstract::Mutationally activated and oncogenic versions of the ras genes were first identified in human tumors in 1982. This discovery prompted great interest in the development of anti-Ras strategies as novel, target-based approaches for cancer treatment. The three human ras genes represent the most frequently mutated oncogene...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章,评审

    doi:10.4161/cbt.306

    authors: Cox AD,Der CJ

    更新日期:2002-11-01 00:00:00

  • Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD.

    abstract::Resistance to apoptosis is one reason for the poor response of malignant brain tumors to therapy. The PPARgamma-modulating drug Troglitazone downregulates the anti-apoptotic FLIP protein and sensitizes glioblastoma cells to apoptosis induced by the death ligand TRAIL. To investigate the molecular basis of an experimen...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.7.12.6966

    authors: Grund K,Ahmadi R,Jung F,Funke V,Gdynia G,Benner A,Sykora J,Walczak H,Joos S,Felsberg J,Reifenberger G,Wiestler OD,Herold-Mende C,Roth W

    更新日期:2008-12-01 00:00:00

  • C7 peptide inhibits hepatocellular carcinoma metastasis by targeting the HGF/c-Met signaling pathway.

    abstract::Hepatocellular carcinoma (HCC), characterized by a high rate of metastasis and recurrence after surgery, is caused by malignant proliferation of hepatocytes with epigenetic and/or genetic mutations. In particular, abnormal activation of the hepatocyte growth factor (HGF)-/c-mesenchymal-epithelial transition receptor (...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.1080/15384047.2019.1647051

    authors: Zhao M,Wang Y,Liu Y,Zhang W,Liu Y,Yang X,Cao Y,Wang S

    更新日期:2019-01-01 00:00:00

  • Sunitinib inhibits papillary thyroid carcinoma with RET/PTC rearrangement but not BRAF mutation.

    abstract::Sunitinib, a multi-targeted tyrosine kinase inhibitor, is frequently incorporated into the management of papillary thyroid carcinoma refractory to standard therapies. Although clinical trials are in progress, the mechanism of action in papillary thyroid carcinomas is not clear, especially regarding the effect on BRAF ...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.12.5.16303

    authors: Jeong WJ,Mo JH,Park MW,Choi IJ,An SY,Jeon EH,Ahn SH

    更新日期:2011-09-01 00:00:00

  • A LIN28B polymorphism predicts for colon cancer survival.

    abstract::The pathogenesis of sporadic colorectal cancer involves distinct pathways, with characteristic genomic alterations. The first pathway, chromosome instability (CIN), is driven by APC mutations and is typified by Kras mutations, p53 mutation/loss of heterozygosity, and deletions at chromosome 18q. The second pathway is ...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.22336

    authors: Ye Y,Madison B,Wu X,Rustgi AK

    更新日期:2012-12-01 00:00:00

  • Low density lipoprotein receptor mediates anti-VEGF effect of lymphocyte T-derived microparticles in Lewis lung carcinoma cells.

    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

    authors: Yang C,Gagnon C,Hou X,Hardy P

    更新日期:2010-09-01 00:00:00

  • Prediction of proapoptotic anticancer therapeutic response in vivo based on cell death visualization and TRAIL death ligand-receptor interaction.

    abstract::Tumor growth is often associated with insufficient apoptosis. The Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) and its proapoptotic receptors death receptor 4 (DR4) and DR5 agonistic monoclonal antibodies are being developed as targeted therapeutics because they kill cancer cells while sparing...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.12.4.17174

    authors: Zhou L,Wang W,Dicker DT,Humphreys RC,El-Deiry WS

    更新日期:2011-08-15 00:00:00

  • Aggressive myeloid leukemia formation is directed by the Musashi 2/Numb pathway.

    abstract::Chronic myeloid leukemia (CML) progresses from a chronic phase to a deadly blast crisis phase. While it is known that BCR-ABL initiates the disease and that secondary molecular and genetic abnormalities likely contribute to progression of the disease to blast crisis, details regarding the mechanism(s) of blast phase p...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.10.10.14010

    authors: Griner LN,Reuther GW

    更新日期:2010-11-15 00:00:00

  • The combination of 5-fluorouracil plus p53 pathway restoration is associated with depletion of p53-deficient or mutant p53-expressing putative colon cancer stem cells.

    abstract::The cancer stem cell hypothesis suggests that rare populations of tumor-initiating cells may be resistant to therapy, lead to tumor relapse and contribute to poor prognosis for cancer patients. We previously demonstrated the feasibility of p53 pathway restoration in p53-deficient tumor cell populations using small mol...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.8.22.10446

    authors: Huang C,Zhang XM,Tavaluc RT,Hart LS,Dicker DT,Wang W,El-Deiry WS

    更新日期:2009-11-01 00:00:00

  • Proteomic profiling: a novel method for differential diagnosis?

    abstract::Tumors with identical phenotype can have markedly different biologic behavior. The differentiation between hemangioblastoma, a benign vascular brain tumor, and renal cell carcinoma (RCC), a malignant tumor that can metastasize to the brain, is a well-known pathological quandary. We report a 59-year-old female with von...

    journal_title:Cancer biology & therapy

    pub_type: 杂志文章

    doi:10.4161/cbt.6.3.3673

    authors: Gläsker S,Lonser RR,Okamoto H,Li J,Jaffee H,Oldfield EH,Zhuang Z,Vortmeyer AO

    更新日期:2007-03-01 00:00:00