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Kras g12c

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https://www.readbyqxmd.com/read/29081842/treating-kras-mutant-nsclc-latest-evidence-and-clinical-consequences
#1
REVIEW
Pilar Garrido, María Eugenia Olmedo, Ana Gómez, Luis Paz Ares, Fernando López-Ríos, Juan Manuel Rosa-Rosa, José Palacios
KRAS mutations represent one of the most prevalent oncogenic driver mutations in non-small cell lung cancer (NSCLC). For many years we have unsuccessfully addressed KRAS mutation as a unique disease. The recent widespread use of comprehensive genomic profiling has identified different subgroups with prognostic implications. Moreover, recent data recognizing the distinct biology and therapeutic vulnerabilities of different KRAS subgroups have allowed us to explore different treatment approaches. Small molecules that selectively inhibit KRAS G12C or use of immune checkpoint inhibitors based on co-mutation status are some examples which anticipate that personalized treatment for this challenging disease is finally on the horizon...
September 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/29018576/key-differences-between-13-kras-mutation-detection-technologies-and-their-relevance-for-clinical-practice
#2
James L Sherwood, Helen Brown, Alessandro Rettino, Amelie Schreieck, Graeme Clark, Bart Claes, Bhuwnesh Agrawal, Ria Chaston, Benjamin S G Kong, Paul Choppa, Anders O H Nygren, Ina L Deras, Alexander Kohlmann
INTRODUCTION: This study assessed KRAS mutation detection and functional characteristics across 13 distinct technologies and assays available in clinical practice, in a blinded manner. METHODS: Five distinct KRAS-mutant cell lines were used to study five clinically relevant KRAS mutations: p.G12C, p.G12D, p.G12V, p.G13D and p.Q61H. 50 cell line admixtures with low (50 and 100) mutant KRAS allele copies at 20%, 10%, 5%, 1% and 0.5% frequency were processed using quantitative PCR (qPCR) (n=3), matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF) (n=2), next-generation sequencing (NGS) (n=6), digital PCR (n=1) and Sanger capillary sequencing (n=1) assays...
2017: ESMO Open
https://www.readbyqxmd.com/read/28961841/dual-met-and-erbb-inhibition-overcomes-intratumor-plasticity-in-osimertinib-resistant-advanced-non-small-cell-lung-cancer-nsclc
#3
A Martinez-Marti, E Felip, J Matito, E Mereu, A Navarro, S Cedrés, N Pardo, A Martinez de Castro, J Remon, J M Miquel, A Guillaumet-Adkins, E Nadal, G Rodriguez-Esteban, O Arqués, R Fasani, P Nuciforo, H Heyn, A Villanueva, H G Palmer, A Vivancos
Background: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. Methods: For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used...
October 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28957417/molecular-subtype-specific-efficacy-of-mek-inhibitors-in-pancreatic-cancers
#4
Diána Brauswetter, Bianka Gurbi, Attila Varga, Edit Várkondi, Richárd Schwab, Gábor Bánhegyi, Orsolya Fábián, György Kéri, István Vályi-Nagy, István Peták
Pancreatic cancer is an increasing cause of cancer related death worldwide. KRAS is the dominant oncogene in this cancer type and molecular rationale would indicate, that inhibitors of the downstream target MEK could be appropriate targeted agents, but clinical trials have failed so far to achieve statistically significant benefit in unselected patients. We aimed to identify predictive molecular biomarkers that can help to define subgroups where MEK inhibitors might be beneficial alone or in combination. Next-generation sequencing data of 50 genes in three pancreatic cancer cell lines (MiaPaCa2, BxPC3 and Panc1) were analyzed and compared to the molecular profile of 138 clinical pancreatic cancer samples to identify the molecular subtypes of pancreatic cancer these cell lines represent...
2017: PloS One
https://www.readbyqxmd.com/read/28781124/potent-and-selective-covalent-quinazoline-inhibitors-of-kras-g12c
#5
Mei Zeng, Jia Lu, Lianbo Li, Frederic Feru, Chunshan Quan, Thomas W Gero, Scott B Ficarro, Yuan Xiong, Chiara Ambrogio, Raymond M Paranal, Marco Catalano, Jay Shao, Kwok-Kin Wong, Jarrod A Marto, Eric S Fischer, Pasi A Jänne, David A Scott, Kenneth D Westover, Nathanael S Gray
Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C...
August 17, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28781083/kras-g12c-drug-development-discrimination-between-switch-ii-pocket-configurations-using-hydrogen-deuterium-exchange-mass-spectrometry
#6
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...
September 5, 2017: Structure
https://www.readbyqxmd.com/read/28692881/detection-of-kras-exon-2-mutations-in-circulating-tumor-cells-isolated-by-the-iset-system-from-patients-with-ras-wild-type-metastatic-colorectal-cancer
#7
Alexios Matikas, Alexandra Voutsina, Eleni Lagoudaki, Dora Hatzidaki, Maria Trypaki, Giannis Stoupis, Maria Tzardi, Dimitrios Mavroudis, Vasilios Georgoulias
INTRODUCTION: The presence of KRAS mutations in patients with metastatic colorectal cancer (mCRC) predicts poor response to agents targeting the EGFR. Even in patients with RAS wild type (WT) tumors, resistance eventually develops due to multiple mechanisms, including the expansion of previously undetected KRAS mutated clones. In this feasibility study, we aimed to detect KRAS exon 2 mutations in serial samples of circulating tumor cells (CTCs) of RAS WT patients with mCRC captured by the Isolation by Size of Epithelial Tumor cells (ISET) system...
August 2017: Translational Oncology
https://www.readbyqxmd.com/read/28662393/ionic-strength-controlled-hybridization-and-stability-of-hybrids-of-kras-dna-single-nucleotides-a-surface-plasmon-resonance-study
#8
N Giamblanco, S Petralia, S Conoci, C Messineo, G Marletta
The discrimination of a fully matched, unlabeled KRAS wild-type (WT) (C-G) target sample with respect to three of the most frequent KRAS codon mutations (G12 S (C-A), G12 R (C-C), G12C (C-T)) was investigated using an optimized detection strategy involving surface plasmon resonance (SPR), based on optimized probe-surface density and ionic strength control. The changes observed in the SPR signal were always larger for WT compared with the single-mismatch target DNA oligonucleotides, and were aligned with the theoretical energy differences between the base pair C-G, C-T, C-A, C-C...
October 1, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28601386/detection-of-alk-and-kras-mutations-in-circulating-tumor-dna-of-patients-with-advanced-alk-positive-nsclc-with-disease-progression-during-crizotinib-treatment
#9
Paola Bordi, Marcello Tiseo, Eleonora Rofi, Iacopo Petrini, Giuliana Restante, Romano Danesi, Marzia Del Re
BACKGROUND: In patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), disease progression occurs after a median of 9 to 10 months of crizotinib treatment. Several mechanisms of resistance have been identified and include ALK mutations and amplification or the activation of bypassing signaling pathways. Rebiopsy in NSCLC patients represents a critical issue and the analysis of circulating cell-free DNA (cfDNA) has a promising role for the identification of resistance mechanisms...
November 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28433077/development-and-clinical-utility-of-a-blood-based-test-service-for-the-rapid-identification-of-actionable-mutations-in-non-small-cell-lung-carcinoma
#10
Hestia Mellert, Trudi Foreman, Leisa Jackson, Dianna Maar, Scott Thurston, Kristina Koch, Amanda Weaver, Samantha Cooper, Nicholas Dupuis, Ubaradka G Sathyanarayana, Jakkie Greer, Westen Hahn, Dawne Shelton, Paula Stonemetz, Gary A Pestano
Nearly 80% of cancer patients do not have genetic mutation results available at initial oncology consultation; up to 25% of patients begin treatment before receiving their results. These factors hinder the ability to pursue optimal treatment strategies. This study validates a blood-based genome-testing service that provides accurate results within 72 hours. We focused on targetable variants in advanced non-small cell lung carcinoma-epidermal growth factor receptor gene (EGFR) variant L858R, exon 19 deletion (ΔE746-A750), and T790M; GTPase Kirsten ras gene (KRAS) variants G12C/D/V; and echinoderm microtubule associated protein like and 4 anaplastic lymphoma receptor tyrosine kinase fusion (EML4-ALK) transcripts 1/2/3...
May 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28407465/kras-g12c-mutation-as-a-poor-prognostic-marker-of-pemetrexed-treatment-in-non-small-cell-lung-cancer
#11
Sehhoon Park, Ji-Yeon Kim, Se-Hoon Lee, Beomseok Suh, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo
BACKGROUND/AIMS: The predictive and prognostic value of KRAS mutation and its type of mutations in non-small cell lung cancer (NSCLC) are controversial. This clinical study was designed to investigate the predictive value of KRAS mutations and its mutation types to pemetrexed and gemcitabine based treatment. METHODS: Advanced NSCLC patients tested for KRAS mutation (n = 334) were retrospectively reviewed and 252 patients with wild type epidermal growth factor receptor and no anaplastic lymphoma kinase fusion were enrolled for the analysis...
May 2017: Korean Journal of Internal Medicine
https://www.readbyqxmd.com/read/28208157/specific-mutations-in-kras-codon-12-are-associated-with-worse-overall-survival-in-patients-with-advanced-and-recurrent-colorectal-cancer
#12
Robert P Jones, Paul A Sutton, Jonathan P Evans, Rachel Clifford, Andrew McAvoy, James Lewis, Abigail Rousseau, Roger Mountford, Derek McWhirter, Hassan Z Malik
BACKGROUND: Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers. However, the prognostic impact of specific point mutations remains less clear. This study assessed the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer. METHODS: Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network. RESULTS: We evaluated the impact of KRAS genotype in 392 patients...
March 28, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28141798/oxidative-dna-damage-induces-hypomethylation-in-a-compromised-base-excision-repair-colorectal-tumourigenesis
#13
Daniela Furlan, Davide Trapani, Enrico Berrino, Carla Debernardi, Mara Panero, Laura Libera, Nora Sahnane, Cristina Riva, Maria Grazia Tibiletti, Fausto Sessa, Anna Sapino, Tiziana Venesio
BACKGROUND: A compromised base excision repair (BER) promotes carcinogenesis by accumulating oxidative DNA-damaged products as observed in MUTYH-associated polyposis, a hereditary colorectal cancer syndrome marked by adenomas and cancers with an accumulation of 8-oxoguanine. Remarkably, DNA global demethylation has been shown to be mediated by BER, suggesting a relevant interplay with early colorectal tumourigenesis. To check this hypothesis, we investigated a cohort of 49 adenomas and 10 carcinomas, derived from 17 MUTYH-associated polyposis patients; as adenoma controls, we used a set of 36 familial adenomatous polyposis and 24 sporadic polyps...
March 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28105276/covalent-guanosine-mimetic-inhibitors-of-g12c-kras
#14
Yuan Xiong, Jia Lu, John Hunter, Lianbo Li, David Scott, Hwan Geun Choi, Sang Min Lim, Anuj Manandhar, Sudershan Gondi, Taebo Sim, Kenneth D Westover, Nathanael S Gray
Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure-activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27870730/cutaneous-sebaceous-lesions-in-a-patient-with-mutyh-associated-polyposis-mimicking-muir-torre-syndrome
#15
Denisa Kacerovska, Lubomir Drlik, Lenka Slezakova, Michal Michal, Jan Stehlik, Monika Sedivcova, Ladislav Hadravsky, Dmitry V Kazakov
A 76-year-old white male with a history of adenocarcinoma of the rectosigmoideum and multiple colonic polyps removed at the age of 38 and 39 years by an abdominoperitoneal amputation and total colectomy, respectively, presented with multiple whitish and yellowish papules on the face and a verrucous lesion on the trunk. The lesions were surgically removed during the next 3 years and a total of 13 lesions were investigated histologically. The diagnoses included 11 sebaceous adenomas, 1 low-grade sebaceous carcinoma, and 1 squamous cell carcinoma...
December 2016: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/27728979/rationale-for-ras-mutation-tailored-therapies
#16
Steven K Montalvo, Lianbo Li, Kenneth D Westover
RAS mutations are among the most common genetic alterations found in cancerous tumors but rational criteria or strategies for targeting RAS-dependent tumors are only recently emerging. Clinical and laboratory data suggest that patient selection based on specific RAS mutations will be an essential component of these strategies. A thorough understanding of the biochemical and structural properties of mutant RAS proteins form the theoretical basis for these approaches. Direct inhibition of KRAS G12C by covalent inhibitors is a notable recent example of the RAS mutation-tailored approach that establishes a paradigm for other RAS mutation-centered strategies...
October 12, 2016: Future Oncology
https://www.readbyqxmd.com/read/27637917/somatic-mutation-analysis-of-kras-braf-her2-and-pten-in-egfr-mutation-negative-non-small-cell-lung-carcinoma-determination-of-frequency-distribution-pattern-and-identification-of-novel-deletion-in-her2-gene-from-indian-patients
#17
Sangeet Bhaumik, Firoz Ahmad, Bibhu Ranjan Das
Somatic mutations of KRAS, BRAF, HER2, PTEN genes are the most important molecular markers after the EGFR gene mutation. The current study evaluated the frequency and distribution pattern of KRAS, BRAF, HER2, PTEN mutation in Indian non-small cell lung carcinoma patients. The frequency of KRAS, BRAF, HER2, PTEN mutations was 6.4 % (14/204), 1.5 % (3/204), 1.5 % (3/204), 0 % (0/204), respectively. KRAS, BRAF, HER2 mutations were more prevalent in males than in females. KRAS and HER2 showed a trend of a higher frequency of mutation in the age group of <60 years, whereas BRAF mutations were more frequent in the age group of ≥60 years...
October 2016: Medical Oncology
https://www.readbyqxmd.com/read/27632281/optimized-multiplex-detection-of-7-kras-mutations-by-taqman-allele-specific-qpcr
#18
Andrea Orue, Manuel Rieber
UNLABELLED: Establishing the KRAS mutational status of tumor samples is essential to manage patients with colorectal or lung cancer, since these mutations preclude treatment with monoclonal anti-epidermal growth factor receptor (EGFR) antibodies. We report an inexpensive, rapid multiplex allele-specific qPCR method detecting the 7 most clinically relevant KRAS somatic mutations with concomitant amplification of non-mutated KRAS in tumor cells and tissues from CRC patients. Positive samples evidenced in the multiplex assay were further subjected to individual allele-specific analysis, to define the specific mutation...
2016: PloS One
https://www.readbyqxmd.com/read/27597976/necessity-of-microdissecting-different-tumor-components-in-pulmonary-tumor-pyrosequencing
#19
Dahui Qin, Zhong Zheng, Shanxiang Shen, Prudence Smith, Farah K Khalil
Microdissection is a useful method in tissue sampling prior to molecular testing. Tumor heterogeneity imposes new challenges for tissue sampling. Different microdissecting methods have been employed in face of such challenge. We improved our microdissection method by separately microdissecting the morphologically different tumor components. This improvement helped the pyrosequencing data analysis of two specimens. One specimen consisted of both adenocarcinoma and neuroendocrine components. When both tumor components were sequenced together for KRAS (Kirsten rat sarcoma viral oncogene homolog) gene mutations, the resulting pyrogram indicated that it was not a wild type, suggesting that it contained KRAS mutation...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27591291/detection-of-kras-mutations-in-circulating-tumor-dna-by-digital-pcr-in-early-stages-of-pancreatic-cancer
#20
Nora Brychta, Thomas Krahn, Oliver von Ahsen
BACKGROUND: Since surgical removal remains the only cure for pancreatic cancer, early detection is of utmost importance. Circulating biomarkers have potential as diagnostic tool for pancreatic cancer, which typically causes clinical symptoms only in advanced stage. Because of their high prevalence in pancreatic cancer, KRAS proto-oncogene, GTPase [KRAS (previous name: Kirsten rat sarcoma viral oncogene homolog)] mutations may be used to identify tumor-derived circulating plasma DNA. Here we tested the diagnostic sensitivity of chip based digital PCR for the detection of KRAS mutations in circulating tumor DNA (ctDNA) in early stage pancreatic cancer...
November 2016: Clinical Chemistry
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