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https://www.readbyqxmd.com/read/28821559/synergy-of-wee1-and-mtor-inhibition-in-mutant-kras-driven-lung-cancers
#1
Josephine Hai, Shengwu Liu, Lauren Bufe, Khanh Do, Ting Chen, Xiaoen Wang, Christine Ng, Shuai Li, Ming-Sound Tsao, Geoffrey I Shapiro, Kwok-Kin Wong
Purpose:KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. <p>Experimental Design: We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28807936/genomic-alterations-in-circulating-tumor-dna-from-diverse-cancer-patients-identified-by-next-generation-sequencing
#2
Maria Schwaederle, Ranajoy Chattopadhyay, Shumei Kato, Paul T Fanta, Kimberly C Banks, In Sil Choi, David E Piccioni, Sadakatsu Ikeda, AmirAli Talasaz, Richard B Lanman, Lyudmila Bazhenova, Razelle Kurzrock
Non-invasive genomic profiling of tumors may be possible with next-generation sequencing (NGS) of blood-derived circulating tumor DNA (ctDNA), but proof of concept in a large cohort <p>of patients with diverse cancers has yet to be reported. Here we report the results of an analysis of plasma-derived ctDNA from 670 patients with diverse cancers.</p> The tumors represented in the patient cohort were mainly gastrointestinal (31.8%), brain (22.7%) or lung (20.7%). ctDNA obtained from most patients (N = 423 (63%)) displayed at least 1 alteration...
August 14, 2017: Cancer Research
https://www.readbyqxmd.com/read/28805806/lung-tumor-exome-files-with-t-cell-receptor-recombinations-a-mouse-model-of-t-cell-infiltrates-reflecting-mutation-burdens
#3
Yaping N Tu, Wei Lue Tong, Timothy J Fawcett, George Blanck
Tumor exomes and RNASeq data were originally intended for obtaining tumor mutations and gene expression profiles, respectively. However, recent work has determined that tumor exome and RNAseq read files contain reads representing T-cell and B-cell receptor (TcR and BcR) recombinations, presumably due to infiltrating lymphocytes. Furthermore, the recovery of immune receptor recombination reads has demonstrated correlations with specific, previously appreciated aspects of tumor immunology. To further understand the usefulness of recovering TcR and BcR recombinations from tumor exome files, we developed a scripted algorithm for recovery of reads representing these recombinations from a previously described mouse model of lung tumorigenesis...
August 14, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28797845/the-hsp90-inhibitor-nvp-auy922-attenuates-intrinsic-pi3k-inhibitor-resistance-in-kras-mutant-non-small-cell-lung-cancer
#4
Kang-Seo Park, Hannah Yang, Junyoung Choi, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Hanwool Jeon, Sang-We Kim, Dae Ho Lee
More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway...
August 7, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28796802/the-prognostic-value-of-kras-mutation-by-cell-free-dna-in-cancer-patients-a-systematic-review-and-meta-analysis
#5
Rongyuan Zhuang, Song Li, Qian Li, Xi Guo, Feng Shen, Hong Sun, Tianshu Liu
KRAS mutation has been found in various types of cancer. However, the prognostic value of KRAS mutation in cell-free DNA (cfDNA) in cancer patients was conflicting. In the present study, a meta-analysis was conducted to clarify its prognostic significance. Literature searches of Cochrane Library, EMBASE, PubMed and Web of Science were performed to identify studies related to KRAS mutation detected by cfDNA and survival in cancer patients. Two evaluators reviewed and extracted the information independently. Review Manager 5...
2017: PloS One
https://www.readbyqxmd.com/read/28790158/lung-tumors-with-distinct-p53-mutations-respond-similarly-to-p53-targeted-therapy-but-exhibit-genotype-specific-statin-sensitivity
#6
Frances K Turrell, Emma M Kerr, Meiling Gao, Hannah Thorpe, Gary J Doherty, Jake Cridge, David Shorthouse, Alyson Speed, Shamith Samarajiwa, Benjamin A Hall, Meryl Griffiths, Carla P Martins
Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear...
August 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28783725/a-braf-kinase-inactive-mutant-induces-lung-adenocarcinoma
#7
Patricia Nieto, Chiara Ambrogio, Laura Esteban-Burgos, Gonzalo Gómez-López, María Teresa Blasco, Zhan Yao, Richard Marais, Neal Rosen, Roberto Chiarle, David G Pisano, Mariano Barbacid, David Santamaría
The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis...
August 10, 2017: Nature
https://www.readbyqxmd.com/read/28783173/synergistic-activity-and-heterogeneous-acquired-resistance-of-combined-mdm2-and-mek-inhibition-in-kras-mutant-cancers
#8
A N Hata, S Rowley, H L Archibald, M Gomez-Caraballo, F M Siddiqui, F Ji, J Jung, M Light, J S Lee, L Debussche, S Sidhu, R I Sadreyev, J Watters, J A Engelman
There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28781083/kras-g12c-drug-development-discrimination-between-switch-ii-pocket-configurations-using-hydrogen-deuterium-exchange-mass-spectrometry
#9
Jia Lu, Rane A Harrison, Lianbo Li, Mei Zeng, Sudershan Gondi, David Scott, Nathanael S Gray, John R Engen, Kenneth D Westover
KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders...
July 25, 2017: Structure
https://www.readbyqxmd.com/read/28780976/prospective-clinical-integration-of-an-amplicon-based-next-generation-sequencing-method-to-select-advanced-non-small-cell-lung-cancer-patients-for-genotype-tailored-treatments
#10
Jon Zugazagoitia, Daniel Rueda, Nuria Carrizo, Ana Belen Enguita, David Gómez-Sánchez, Asunción Díaz-Serrano, Elisabeth Jiménez, Antonio Mérida, Rosa Calero, Ricardo Lujan, Eduardo De Miguel, Pablo Gámez, Vicente Díaz-Hellín, Juan Antonio Nuñez, Lara Iglesias, Irene Ferrer, Luis Paz-Ares, Santiago Ponce-Aix
INTRODUCTION: A substantial fraction of non-small-cell lung cancers (NSCLCs) harbor targetable genetic alterations. In this study, we analyzed the feasibility and clinical utility of integrating a next-generation sequencing (NGS) panel into our routine lung cancer molecular subtyping algorithm. PATIENTS AND METHODS: After routine pathologic and molecular subtyping, we implemented an amplicon-based gene panel for DNA analysis covering mutational hot spots in 22 cancer genes in consecutive advanced-stage NSCLCs...
June 23, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28765579/inhibition-of-akt1-signaling-promotes-invasion-and-metastasis-of-non-small-cell-lung-cancer-cells-with-k-ras-or-egfr-mutations
#11
Guanhua Rao, Mariaelena Pierobon, In-Kyu Kim, Wei-Hsun Hsu, Jianghong Deng, Yong-Wha Moon, Emanuel F Petricoin, Yu-Wen Zhang, Yisong Wang, Giuseppe Giaccone
Accumulating evidence supports a role of the PI3K-AKT pathway in the regulation of cell motility, invasion and metastasis. AKT activation is known to promote metastasis, however under certain circumstances, it also shows an inhibitory activity on metastatic processes, and the cause of such conflicting results is largely unclear. Here we found that AKT1 is an important regulator of metastasis and down-regulation of its activity is associated with increased metastatic potential of A549 cells. Inhibition of AKT1 enhanced migration and invasion in KRAS- or EGFR-mutant non-small cell lung cancer (NSCLC) cells...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28762849/first-line-carboplatin-pemetrexed-and-panitumumab-in-patients-with-advanced-non-squamous-kras-wild-type-wt-non-small-cell-lung-cancer-nsclc
#12
David R Spigel, Tarek M Mekhail, David Waterhouse, Terence Hadley, Charles Webb, Howard A Burris, John D Hainsworth, F Anthony Greco
BACKGROUND: We added panitumumab to standard combination chemotherapy as first-line treatment for patients with advanced KRAS WT non-squamous NSCLC. METHODS: Patients received panitumumab 9 mg/kg IV, pemetrexed 500 mg/m(2) IV, and carboplatin AUC = 6 IV every 21 days. After 6 cycles, maintenance therapy with panitumumab and pemetrexed was administered every 21 days until progressive disease or unacceptable toxicity. RESULTS: 29 of 66 patients (44%) had objective responses...
August 1, 2017: Cancer Investigation
https://www.readbyqxmd.com/read/28762087/non-small-cell-lung-cancer-nsclc-harboring-alk-translocations-clinical-characteristics-and-management-in-a-real-life-setting-a-french-retrospective-analysis-gfpc-02-14-study
#13
Jean-Bernard Auliac, Isabelle Monnet, Catherine Dubos-Arvis, Anne Marie Chiappa, Nathalie Baize, Suzana Bota, Alain Vergnenegre, Helene Doubre, Chrystele Locher, Acya Bizieux, Gilles Robinet, Christos Chouaid
BACKGROUND: Chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK) are rare oncogenic events found in 3-5% of non-small-cell lung cancers (NSCLC). Limited data have been published on the management of these patients outside clinical trials. OBJECTIVE: To investigate the clinical characteristics and management of patients with NSCLC harboring ALK translocations (ALK+) in a real-life setting in France. METHODS: This multicenter, observational, retrospective study included all NSCLC patients harboring ALK translocations diagnosed in participating centers between January 2012 and December 2014...
July 31, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28760854/oncogenic-kras-and-p53-loss-drive-gastric-tumorigenesis-in-mice-that-can-be-attenuated-by-e-cadherin-expression
#14
Jacob Till, Changhwan Yoon, Bang-Jin Kim, Kerry C Roby, Prince Addai, Evan Jonokuchi, Laura H Tang, Sam S Yoon, Sandra Ryeom
Gastric adenocarcinoma (GA) is the third leading cause of cancer-related death worldwide, but no models exist to readily investigate distant metastases which are mainly responsible for mortality in this disease. Here we report the development of a genetically engineered mouse model of GA tumorigenesis based on Kras(G12D) expression plus inactivation of E-cadherin (Cdh1) and p53 in the gastric parietal cell lineage. Intestinal and diffuse gastric tumors arise rapidly in this model, which displays a median survival of 76 days...
July 31, 2017: Cancer Research
https://www.readbyqxmd.com/read/28759160/a-quadruple-action-pt-iv-prodrug-with-anticancer-activity-against-kras-mutated-cancer-cell-lines
#15
Dan Gibson, Emanuele Petruzzella, Jeremy Phillip Braude, Janice Aldrich-Wright, Valentina Gandin
We developed a novel Pt(IV) prodrug that simultaneously releases four different bioactive moieties inside the cancer cell acting like a cluster bomb. Its cytotoxicity against 2D and 3D cancer cells is significantly better than cisplatin. It is 200-450 fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40 fold more selective towards KRAS mutated cells compared to non-cancerous. This is important since RAS proteins play a role in regulating cell differentiation, proliferation, and survival and KRAS is mutated in 90% of pancreatic adenocarcinomas, 45% of colorectal cancers, and 35% of lung adenocarcinomas...
July 31, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28755461/variation-in-organ-specific-pik3ca-and-kras-mutant-levels-in-normal-human-tissues-correlates-with-mutation-prevalence-in-corresponding-carcinomas
#16
Barbara L Parsons, Karen L McKim, Meagan B Myers
Large-scale sequencing efforts have described the mutational complexity of individual cancers and identified mutations prevalent in different cancers. As a complementary approach, allele-specific competitive blocker PCR (ACB-PCR) is being used to quantify levels of hotspot cancer driver mutations (CDMs) with high sensitivity, to elucidate the tissue-specific properties of CDMs, their occurrence as tumor cell subpopulations, and their occurrence in normal tissues. Here we report measurements of PIK3CA H1047R mutant fraction (MF) in normal colonic mucosa, normal lung, colonic adenomas, colonic adenocarcinomas, and lung adenocarcinomas...
July 29, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28754670/gemcitabine-and-chk1-inhibitor-azd7762-synergistically-suppress-the-growth-of-lkb1-deficient-lung-adenocarcinoma
#17
Kwok-Kin Wong, Yan Liu, Yuyang Li, Xiaoen Wang, Feiyang Liu, Peng Gao, Max M Quinn, Fei Li, Ashley A Merlino, Cyril H Benes, Qingsong Liu, Nathanael S Gray
Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model (GEMM) of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in Kras/p53/Lkb1 tumors, synergizing with the DNA damaging drug gemcitabine to reduce tumor size in these models...
July 28, 2017: Cancer Research
https://www.readbyqxmd.com/read/28746882/a-landscape-of-therapeutic-cooperativity-in-kras-mutant-cancers-reveals-principles-for-controlling-tumor-evolution
#18
Grace R Anderson, Peter S Winter, Kevin H Lin, Daniel P Nussbaum, Merve Cakir, Elizabeth M Stein, Ryan S Soderquist, Lorin Crawford, Jim C Leeds, Rachel Newcomb, Priya Stepp, Catherine Yip, Suzanne E Wardell, Jennifer P Tingley, Moiez Ali, Mengmeng Xu, Meagan Ryan, Shannon J McCall, Autumn J McRee, Christopher M Counter, Channing J Der, Kris C Wood
Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28744021/thy-1-cancer-associated-fibroblasts-adversely-impact-lung-cancer-prognosis
#19
Mark J Schliekelman, Chad J Creighton, Brandi N Baird, Yulong Chen, Priyam Banerjee, Neus Bota-Rabassedas, Young-Ho Ahn, Jonathon D Roybal, Fengju Chen, Yiqun Zhang, Dhruva K Mishra, Min P Kim, Xin Liu, Barbara Mino, Pamela Villalobos, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio I Wistuba, Samir M Hanash, Jonathan M Kurie
Cancer-associated fibroblasts (CAFs) regulate diverse intratumoral biological programs and can promote or inhibit tumorigenesis, but those CAF populations that negatively impact the clinical outcome of lung cancer patients have not been fully elucidated. Because Thy-1 (CD90) marks CAFs that promote tumor cell invasion in a murine model of Kras(G12D)-driven lung adenocarcinoma (Kras(LA1)), here we postulated that human lung adenocarcinomas containing Thy-1(+) CAFs have a worse prognosis. We first examined the location of Thy-1(+) CAFs within human lung adenocarcinomas...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28710768/panobinostat-sensitizes-kras-mutant-non-small-cell-lung-cancer-to-gefitinib-by-targeting-taz
#20
Wen-Ying Lee, Pin-Cyuan Chen, Wen-Shin Wu, Han-Chung Wu, Chun-Hsin Lan, Yen-Hua Huang, Chia-Hsiung Cheng, Ku-Chung Chen, Cheng-Wei Lin
Mutation of KRAS in non-small-cell lung cancer (NSCLC) shows a poor response to epidermal growth factor receptor (EGFR) inhibitors and chemotherapy. Currently, there are no direct anti-KRAS therapies available. Thus, new strategies have emerged for targeting KRAS downstream signaling. Panobinostat is a clinically available histone deacetylase inhibitor for treating myelomas and also shows potentiality in NSCLC. However, the therapeutic efficacy of panobinostat against gefitinib-resistant NSCLC is unclear. In this study, we demonstrated that panobinostat overcame resistance to gefitinib in KRAS-mutant/EGFR-wild-type NSCLC...
July 14, 2017: International Journal of Cancer. Journal International du Cancer
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