Abstract:
:Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. SIGNIFICANCE: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation.See related commentary by Whitehead and Sebolt-Leopold, p. 4042.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Hanrahan AJ,Sylvester BE,Chang MT,Elzein A,Gao J,Han W,Liu Y,Xu D,Gao SP,Gorelick AN,Jones AM,Kiliti AJ,Nissan MH,Nimura CA,Poteshman AN,Yao Z,Gao Y,Hu W,Wise HC,Gavrila EI,Shoushtari AN,Tiwari S,Viale A,Abddoi
10.1158/0008-5472.CAN-20-0865subject
Has Abstractpub_date
2020-10-01 00:00:00pages
4233-4243issue
19eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-20-0865journal_volume
80pub_type
评论,杂志文章相关文献
CANCER RESEARCH文献大全abstract::ZR-75-1, a human breast cancer cell line, has been grown in hormone-supplemented medium without serum. The factors required for optimal growth include 17beta-estradiol, insulin, transferrin, dexamethasone, and L-triiodothyronine. If estradiol, insulin, or L-triiodothyronine is omitted, cells cease division within 7 da...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1978-11-01 00:00:00
abstract::Migration from the primary tumor is a crucial step in the metastatic cascade. Cells with various degrees of adhesion and motility migrate and are launched into the bloodstream as single circulating tumor cells (CTC) or multicellular CTC clusters. The frequency and size distributions of these clusters have been recentl...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-19-1726
更新日期:2019-11-01 00:00:00
abstract::Tumor cell interaction with endothelial cells is a crucial step leading to organ-selective metastasis. Adhesion of murine B16 amelanotic melanoma cells (B16a) to murine microvascular endothelial cells (CD3) was enhanced, in a dose- and time-dependent manner, by pretreating CD3 cells with 12(S)-hydroperoxyeicosatetraen...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-02-15 00:00:00
abstract::Chronic exposure to UV radiation (UVR), especially in the UVA (315-400 nm) and UVB (280-315 nm) spectrum of sunlight, is the major risk factor for the development of nonmelanoma skin cancer. UVR is a complete carcinogen, which both initiates and promotes carcinogenesis. We found that protein kinase C epsilon (PKCepsil...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-1881
更新日期:2004-11-01 00:00:00
abstract::The multistage process of cancer formation is driven by the progressive acquisition of somatic mutations. Replication stress creates genomic instability in mammals. Using a well-defined multistep leukemia model driven by Spi-1/PU.1 overexpression in the mouse and Spi-1/PU.1-overexpressing human leukemic cells, we inve...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-4691
更新日期:2010-09-01 00:00:00
abstract::Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient cha...
journal_title:Cancer research
pub_type: 杂志文章,多中心研究
doi:10.1158/0008-5472.CAN-19-1554
更新日期:2019-10-15 00:00:00
abstract::The concentration of potassium (K+) and sodium (Na+) was measured in breast cyst fluid (BCF) from 611 cysts greater than 3 ml aspirated in 520 women with gross cystic disease of the breast. These women were enrolled, from 1983 on, in a cohort study aimed at assessing the relationship between cyst type, as defined by t...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1992-04-01 00:00:00
abstract::In Drosophila melanogaster, the wings apart-like (wapl) gene encodes a protein that regulates heterochromatin structure. Here, we characterize a novel human homologue of wapl (termed human WAPL; hWAPL). The hWAPL mRNA was predominantly expressed in uterine cervical cancer, with weak expression in all other normal and ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-03-3822
更新日期:2004-05-15 00:00:00
abstract::In order to test the contention that metastasis is a selective process and that therefore metastases might show a more restricted pattern of phenotypic and genotypic characteristics than primary tumors, we compared the expression of carcinoembryonic antigen, Ca 19-9, secretory component, serotonin, and mucin productio...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-08-15 00:00:00
abstract::Although accumulating evidence indicates that chronic lymphocytic leukemia (CLL) is a disease with appreciable cell dynamics, it remains uncertain whether this also applies to patients with stable disease. In this study, (2)H(2)O was administered to a clinically homogeneous cohort of nine stable, untreated CLL patient...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-2325
更新日期:2008-12-15 00:00:00
abstract::Early phase evaluation of anticancer drugs has traditionally used toxicity (usually hematological) rather than efficacy end points to establish appropriate dosing schedules. To establish a biochemical efficacy end point for overcoming alkylguanine DNA alkyltransferase (AGT)-mediated tumor cell resistance to 1,3-bis(2-...
journal_title:Cancer research
pub_type: 临床试验,杂志文章
doi:
更新日期:1999-05-15 00:00:00
abstract::Concanavalin A-induced blastogenesis of spleen lymphocytes was significantly inhibited when lymphocytes from rats on a high-polyunsaturated-fat diet were compared to lymphocytes from rats on a low-fat diet. Responsiveness was dependent on source of serum since lymphocytes from rats fed a low-fat diet were suppressed i...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1979-09-01 00:00:00
abstract::Hereditary renal carcinoma (RC) in the rat, originally reported by Eker in 1954, is an example of a Mendelian dominant predisposition to a specific cancer in an experimental animal. We previously reported that ionizing radiation induces additional tumors in a linear dose-response relationship, suggesting that in heter...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-05-15 00:00:00
abstract::Mechanisms governing inducible resistance to ionizing radiation in untransformed epithelial cells pre-exposed to low-dose ionizing radiation (LDIR; =10 cGy) are not well understood. The present study provides evidence that pre-exposure to 10 cGy X-rays increases clonogenic survival of mouse skin JB6P+ epithelial cel...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-2728
更新日期:2007-04-01 00:00:00
abstract::Mechanism, in addition to protein kinase C activation may mediate 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated differentiation of leukemic cells. We compared the effect of pretreating intact monoblastoid U937 cells with TPA or the diacylglycerol derivative, 1-oleoyl-2-acetylglycerol (OAG), by studying the pro...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1987-07-01 00:00:00
abstract::Intracarotid infusion of bradykinin selectively increases the delivery of compounds into brain tumors. This study sought to determine the role of cyclic GMP in increased permeability across the blood-tumor barrier (BTB) after infusion of bradykinin. In permeability studies, 186 Wistar rats with RG2 gliomas and C6 glio...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1998-03-01 00:00:00
abstract::Epidemiologic data and animal experiments suggest that dietary fat may influence risk of breast cancer. To determine whether intervention with a low-fat, high-carbohydrate diet would reduce breast cancer incidence in women at increased risk of the disease, we carried out a randomized controlled trial in Canada. We rec...
journal_title:Cancer research
pub_type: 杂志文章,随机对照试验
doi:10.1158/0008-5472.CAN-10-1436
更新日期:2011-01-01 00:00:00
abstract::The present study was designed to investigate the effect of selenium supplementation on dimethylbenz[a]anthracene-induced mammary tumorigenesis in female Sprague-Dawley rats fed either a 5 or 25% corn oil diet, denoted as low fat (LF) or high fat (HF), respectively. Selenium supplementation of LF and HF diets were beg...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-07-01 00:00:00
abstract::The conversion of transforming growth factor beta (TGF-beta) from a tumor suppressor to a tumor promoter occurs frequently during mammary tumorigenesis, yet the molecular mechanisms underlying this phenomenon remain undefined. We show herein that TGF-beta repressed nuclear factor-kappaB (NF-kappaB) activity in normal ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-3094
更新日期:2008-03-01 00:00:00
abstract::Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy ove...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-2000
更新日期:2007-02-01 00:00:00
abstract::Thirteen variables were evaluated for their significance in predicting the survival of 148 patients in a retrospective study with clinical Stage I cutaneous malignant melanoma. The variables studied were histological type, tumor thickness, level of invasion, mitotic activity, pigmentation type, existence of ulceration...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-06-01 00:00:00
abstract::Mutations in the human adenomatous polyposis (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. The APC gene is a tumor suppressor that has been termed the "gatekeeper gene" for colon ca...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-02-15 00:00:00
abstract::2-Methoxyestradiol (2ME(2)), a physiologic metabolite of 17beta-estradiol (estrogen), has emerged as a promising cancer therapy because of its potent growth-inhibitory and proapoptotic effects on both endothelial and tumor cells. 2ME(2) also suppresses osteoclast differentiation and induces apoptosis of mature osteocl...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-1362
更新日期:2007-11-01 00:00:00
abstract::Bloom syndrome is an autosomal recessive disorder whose characteristics include an increased risk for many types of cancers. In contrast to the homozygous mutations of Bloom syndrome, heterozygous carriers of BLM mutations may be at increased risk for developing colorectal cancer. We have screened 2,333 Jewish individ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-04-15 00:00:00
abstract::We analyzed the epidermal growth factor receptor gene using a complementary DNA probe of the epidermal growth factor receptor gene in 21 uncultured primary breast carcinomas and found that the gene was amplified in three of these tumors. We further demonstrated by immunohistochemistry using a monoclonal antibody to th...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-01-01 00:00:00
abstract::Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent coculturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis and that indu...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-12-3228
更新日期:2013-09-15 00:00:00
abstract::DNA mismatch repair (MMR) plays a key role in the cytotoxic response of human cells to methylating agents, however, the cascade of events leading to cell cycle arrest and cell death has yet to be characterized. We studied the role of MMR in the transcriptional response to DNA methylation damage in two human cellular m...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-12-01 00:00:00
abstract::A founder allele in the CHEK2 gene (1100delC) has been associated with an elevated risk of breast cancer. This allele is responsible for the majority of CHEK2-associated breast cancers in women from northern European countries; however, within Europe, it seems to be rare in countries that are close to the Mediterranea...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-5187
更新日期:2008-04-01 00:00:00
abstract::KLF4/GLKF4 is a transcription factor that can have divergent functions in different malignancies. The role of KLF4 in prostate cancer etiology remains unclear. We have recently reported that small double-stranded RNA can induce gene expression by targeting promoter sequence in a phenomenon referred to as RNA activatio...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-10-2414
更新日期:2010-12-15 00:00:00
abstract::The increased proteolytic activity of membrane-bound and secreted proteases on the surface of cancer cells and in the transformed stroma is a common characteristic of aggressive metastatic prostate cancer. We describe here the development of an active site-specific probe for detecting a secreted peritumoral protease e...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-2185
更新日期:2015-04-01 00:00:00