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 Therjournal_title
Cancer biology & therapyauthors
Nalluri S,Peirce SK,Tanos R,Abdella HA,Karmali D,Hogarty MD,Goldsmith KCdoi
10.1080/15384047.2014.1002333subject
Has Abstractpub_date
2015-01-01 00:00:00pages
276-86issue
2eissn
1538-4047issn
1555-8576journal_volume
16pub_type
杂志文章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
更新日期:2018-02-01 00:00:00
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
更新日期:2009-07-01 00:00:00
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
更新日期:2020-10-02 00:00:00
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
更新日期:2010-06-15 00:00:00
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
更新日期:2016-12-01 00:00:00
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
更新日期:2015-01-01 00:00:00
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
更新日期:2005-12-01 00:00:00
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
更新日期:2009-04-01 00:00:00
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
更新日期:2006-04-01 00:00:00
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:
更新日期:2003-11-01 00:00:00
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
更新日期:2008-03-01 00:00:00
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
更新日期:2010-11-01 00:00:00
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
更新日期:2018-01-02 00:00:00
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
更新日期:2006-08-01 00:00:00
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
更新日期:2006-11-01 00:00:00
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
更新日期:2020-05-03 00:00:00
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
更新日期:2009-06-01 00:00:00
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
更新日期:2021-01-02 00:00:00
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
更新日期:2009-11-01 00:00:00
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
更新日期:2016-10-02 00:00:00
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
更新日期:2002-11-01 00:00:00
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
更新日期:2008-12-01 00:00:00
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
更新日期:2019-01-01 00:00:00
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
更新日期:2011-09-01 00:00:00
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
更新日期:2012-12-01 00:00:00
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
更新日期:2010-09-01 00:00:00
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
更新日期:2011-08-15 00:00:00
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
更新日期:2010-11-15 00:00:00
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
更新日期:2009-11-01 00:00:00
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
更新日期:2007-03-01 00:00:00