Abstract：
:Non-small cell lung cancer patients carrying oncogenic EGFR mutations initially respond to EGFR-targeted therapy, but later elicit minimal response due to dose-limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets EGFR-activating mutations arising de novo and upon resistance acquisition, while sparing wild-type (WT) EGFR. EGF816 potently inhibited the most common EGFR mutations L858R, Ex19del, and T790M in vitro, which translated into strong tumor regressions in vivo in several patient-derived xenograft models. Notably, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 treatment led to minimal inhibition of WT EGFR and was well tolerated. In single-dose studies, EGF816 provided sustained inhibition of EGFR phosphorylation, consistent with its ability for irreversible binding. Furthermore, combined treatment with EGF816 and INC280, a cMET inhibitor, resulted in durable antitumor efficacy in a xenograft model that initially developed resistance to first-generation EGFR inhibitors via cMET activation. Thus, we report the first preclinical characterization of EGF816 and provide the groundwork for its current evaluation in phase I/II clinical trials in patients harboring EGFR mutations, including T790M.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Jia Y,Juarez J,Li J,Manuia M,Niederst MJ,Tompkins C,Timple N,Vaillancourt MT,Pferdekamper AC,Lockerman EL,Li C,Anderson J,Costa C,Liao D,Murphy E,DiDonato M,Bursulaya B,Lelais G,Barretina J,McNeill M,Epple R,Mardoi
10.1158/0008-5472.CAN-15-2581subject
Has Abstractpub_date
2016-03-15 00:00:00pages
1591-602issue
6eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-15-2581journal_volume
76pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract：:Individual human infiltrating ductal carcinomas and fibroadenomas were sectioned frozen to yield an alternating sequence of stained and lyophilized material. Stained preparations were used as references permitting microdissection of regions of tumor involvement in the corresponding dried sections. Tissues quantities o...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1982-05-01 00:00:00
abstract：:Although androgen ablation therapy is effective in treating primary prostate cancers, a significant number of patients develop incurable castration-resistant disease. Recent studies have suggested a potential synergy between vaccination and androgen ablation, yet the enhanced T-cell function is transient. Using a defi...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-11-2499
更新日期：2012-04-15 00:00:00
abstract：:Blood vessels deliver oxygen and nutrients to tissues, and vascular networks are spatially organized to meet the metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally i...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-0412
更新日期：2010-08-01 00:00:00
abstract：:Myeloid-derived suppressor cells (MDSC) expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. They therefore represent a major obstacle for successful cancer immunotherapy. Different strategies have thus been explored to deplete and/or inactivate MDS...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-13-1545
更新日期：2014-01-01 00:00:00
abstract：:Transforming growth factor beta-1 (TGF-beta1) is a potent inhibitor of hepatocyte growth both in vivo and in vitro. In this study, we analyzed the effects of TGF-beta1 on both naturally occurring and diethylnitrosamine-induced hepatocarcinogenesis using single transgenic TGF-beta1 and double transgenic c-myc/TGF-beta1...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1997-06-01 00:00:00
abstract：:The specific binding of labeled porcine insulin, human prolactin, and human growth hormone was studied in 63 human breast tumors and 15 nonmalignant breast tissues. Most (90%) of the tumors demonstrated significant binding of insulin, as did 80% of nonmalignant tissues. Autoradiographic studies indicated that insulin ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1977-07-01 00:00:00
abstract：:The eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in human cancers in relation to disease progression and drives cellular transformation, tumorigenesis, and metastatic progression in experimental models. Enhanced eIF4E function results from eIF4E overexpression and/or activation of th...
journal_title：Cancer research
pub_type： 杂志文章,评审
doi：10.1158/0008-5472.CAN-07-5635
更新日期：2008-02-01 00:00:00
abstract：:Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and constitutes 15% of adult leukemias. Although overall prognosis for pediatric ALL is favorable, high-risk pediatric patients and most adult patients have significantly worse outcomes. Multiagent chemotherapy is standard of care for both pedi...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-2238
更新日期：2011-02-15 00:00:00
abstract：:The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in patients with VHL disease and in the majority of patients with sporadic clear cell renal carcinoma (RCC). Overexpression of transforming growth factor (TGF) beta1 has been observed in patients with several cancers, including RCCs, with serum and urine lev...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1999-05-01 00:00:00
abstract：:Lipid peroxidation is considered a unifying mechanistic pathway through which known risk factors induce renal cell carcinoma (RCC). We hypothesized that genes selected a priori for their role in lipid peroxidation would modify cancer risk. We genotyped 635 single nucleotide polymorphisms (SNP) in 38candidate genes in ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-09-1734
更新日期：2009-10-15 00:00:00
abstract：:B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell-mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished sur...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-07-1068
更新日期：2007-08-15 00:00:00
abstract：:Polycyclic aromatic hydrocarbons, possible human breast carcinogens, are metabolized by cytochrome P4501A1 (CYP1A1) and glutathione S-transferase (GSTM1). A CYP1A1 polymorphism (isoleucine to valine substitution in exon 7) or the null allele for GSTM1 may affect the mutagenic potential of polycyclic aromatic hydrocarb...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1995-08-15 00:00:00
abstract：:Forty patients with relapsed (26) or refractory (14) myeloma were treated with epirubicin of doses of 75, 90, 105, and 120 mg/m2 in groups of 6 or more patients to test for response, maximum tolerated dose, and toxicity. Thirteen patients had received prior doxorubicin and were included in the dose findings part of th...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1988-11-01 00:00:00
abstract：:Chromosomal aberrations associated with lung cancer are frequently observed in the long arm of chromosome 6. A candidate susceptibility locus at 6q23-25 for lung cancer was recently identified; however, no tumor suppressor genes inactivated by mutation have been identified in this locus. Genetic, epigenetic, gene expr...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-07-6325
更新日期：2008-03-15 00:00:00
abstract：:It has been shown that the systemic administration of lymphokine-activated killer (LAK) cells with recombinant interleukin 2 (RIL-2) is effective in reducing the number of established pulmonary and hepatic metastases in murine models. Similarly, this modality of therapy has been proven effective against certain select...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1989-05-01 00:00:00
abstract：:There is evidence from experimental work that hypoxia induces apoptosis in apoptosis-sensitive neoplastic cells and that this apoptotic sensitivity is lost during malignant progression. Oxygenation profiles and apoptotic indices in human squamous cell cancer of the uterine cervix have been determined, and a subgroup o...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1999-09-15 00:00:00
abstract：:Osteoprotegerin (OPG), a novel, secreted tumor necrosis factor receptor family member that inhibits osteoclast formation and activity was examined for its activity in a syngeneic tumor model of humoral hypercalcemia of malignancy. Normal mice bearing Colon-26 tumors develop increases in both parathyroid hormone-relate...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2000-02-15 00:00:00
abstract：:The phospholipids of both mitochondrial and microsomal membranes from normal liver, host liver, and Morris hepatoma 7777 were isolated, separated, and quantitated. The total as well as the individual fatty acid concentrations and compositions were determined. The total phosphlipids isolated from tumor mitochondria wer...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1977-02-01 00:00:00
abstract：:Understanding the intratumoral heterogeneity of hepatocellular carcinoma is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diver...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-16-2822
更新日期：2017-05-01 00:00:00
abstract：:The cytokine-inducible endothelial cell adhesion receptor E-selectin has been implicated in cancer metastasis. Previously, we reported that experimental liver metastasis of Lewis lung carcinoma subline H-59 cells could be abrogated in animals treated with an anti-E-selectin antibody. To gain further insight into the f...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1999-03-15 00:00:00
abstract：:Friend erythroleukemia cells can be induced to undergo erythroid differentiation by a variety of unrelated compounds. The fact that sodium butyrate causes reversible alterations in growth, morphology, and biochemistry in many cell systems prompted us to reexamine its pattern of induction of differentiation and to comp...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1987-01-15 00:00:00
abstract：:Reversal of the drug resistance phenotype by the use of agents which induce cell differentiation offers an experimental approach to the study of chemoresistance. In numerous in vitro models, alpha-interferon (alpha-IFN) has been shown to induce phenotypical changes and to modulate the growth of cancer cells. The aim o...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1991-09-15 00:00:00
abstract：:To identify mechanisms of camptothecin (CPT) resistance and the relationship between CPT-resistant cells and other anticancer agents, a CPT-resistant cell line (CPT30) and its partial revertant cell line (CPT30R) were established from a human nasopharyngeal carcinoma cell line (HONE-1). CPT30 and CPT30R cells displaye...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2002-07-01 00:00:00
abstract：:Integral membrane proteins are visualized as intramembrane particles (IMP; also called membrane-associated particles) at the cleaved surfaces of freeze-fractured plasma membranes. Topographical distributions of the IMP of urothelial cell membranes in normal human bladder and for a small series of low-grade noninvasive...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1976-07-01 00:00:00
abstract：:To identify methylation-mediated silencing of genes in hepatocellular carcinoma (HCC), we surveyed genes induced by treatment with 5-aza-2'-deoxycytidine (5-Aza-CdR) in six human hepatoma cell lines using cDNA microarray analysis and determined the methylation status of 5' CpG islands by bisulfite DNA sequencing or me...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2003-12-15 00:00:00
abstract：:Caffeine is a key component of many popular drinks, especially tea and coffee. Previous reports have shown that caffeine may contribute to the chemopreventive effect of tea in animals. Here, we report that treatment with low concentrations of caffeine induced apoptosis in JB6 Cl41 cells. JB6 Cl41 cells were starved in...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2003-08-01 00:00:00
abstract：:Using Mth1 and Ogg1 knockout mice, we evaluated the roles of these enzymes to prevent tumorigenesis and the accumulation of 8-oxoguanine (8-oxoG) in DNA. We found that lung adenoma/carcinoma spontaneously developed in Ogg1 knockout mice approximately 1.5 years after birth in which 8-oxoG was found to accumulate in the...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2003-03-01 00:00:00
abstract：:The effect of the potent angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470), a semisynthetic analogue of fumagillin, on tumor growth and metastasis was studied using rodent tumors. Injection of TNP-470 s.c. inhibited tumor growth in a dose-dependent manner, and the tumor sizes of B16BL6 melanoma, M5...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1993-09-15 00:00:00
abstract：:The role of active oxygen species and lipid peroxidation in the antitumor effect of hyperthermia was studied in an experimental rabbit model. VX2 tumors were transplanted into rabbit hind legs, and the effect of hyperthermia on tumor growth was measured at 7 and 14 days after heating. As an index of lipid peroxidation...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1993-05-15 00:00:00
abstract：:Using computerized pharmacy records from 1969 to 1973 for a cohort of 143,574 members of the Kaiser Permanente Medical Care Program, we have been testing associations of 215 drugs or drug groups with subsequent incidence of cancer at 56 sites. This paper presents findings with follow-up through 1984. There were 227 st...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1989-10-15 00:00:00
