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Kras g12c

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
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...
April 14, 2017: Korean Journal of Internal Medicine
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
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
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
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
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
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
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
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
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...
September 2, 2016: Clinical Chemistry
Candice Y Wilson, Peter Tolias
Mutated RAS is present in 30% of human tumors, appearing in 90% of pancreatic, 45% of colon and 35% of lung cancers. These high occurrences make RAS one of the most important drug targets in oncology. Three decades of effort to target RAS have been unsuccessful in generating drug therapies suggesting that it might represent an 'undruggable' target. However, recent reports highlighting new approaches for targeting RAS have uncovered more information on protein structure and identified new binding pockets. Efforts to target the KRAS G12C mutation specifically have shown promising results whereas other approaches have targeted various protein complexes...
December 2016: Drug Discovery Today
Xiufeng Pang, Mingyao Liu
Ras proteins are considered as the founding members of a large superfamily of small GTPases that control fundamental cellular functions. Mutationally activated RAS genes were discovered in human cancer cells more than 3 decades ago, but intensive efforts on Ras structure, biochemistry, function and signaling continue even now. Because mutant Ras proteins are inherently difficult to inhibit and have yet been therapeutically conquered, it was designated as "the Everest of oncogenes" in the cancer genome landscape, further promoting a "renaissance" in RAS research...
July 27, 2016: Small GTPases
D P Modest, I Ricard, V Heinemann, S Hegewisch-Becker, W Schmiegel, R Porschen, S Stintzing, U Graeven, D Arnold, L F von Weikersthal, C Giessen-Jung, A Stahler, H J Schmoll, A Jung, T Kirchner, A Tannapfel, A Reinacher-Schick
BACKGROUND: To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy. PATIENTS AND METHODS: A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan-Meier method, log-rank tests and Cox models. RESULTS: In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Stéphane Renaud, Joseph Seitlinger, Pierre-Emmanuel Falcoz, Mickaël Schaeffer, Anne-Claire Voegeli, Michèle Legrain, Michèle Beau-Faller, Gilbert Massard
BACKGROUND: We aimed to evaluate whether EGFR mutations (mEGFR) and KRAS amino acid substitutions can predict first site of recurrence or metastasis after non-small-cell lung cancer (NSCLC) surgery. METHODS: Data were reviewed from 481 patients who underwent thoracic surgery for NSCLC between 2007 and 2012. RESULTS: Patients with KRAS G12C developed significantly more bone metastases compared with the remainder of the cohort (59% vs 16%, P<0...
July 26, 2016: British Journal of Cancer
Laura Brunelli, Elisa Caiola, Mirko Marabese, Massimo Broggini, Roberta Pastorelli
Oncogenes induce metabolic reprogramming on cancer cells. Recently, G12C KRAS mutation in isogenic NSCLC cell line has been shown to be a key player in promoting metabolic rewiring mainly through the regulation of glutamine metabolism to fuel growth and proliferation. Even though cell lines possessing many of the genetic backgrounds of the primary cancer they derive from could be a valuable pre-clinical model, they do not have the additional complexity present in the whole tumor that impact metabolism. This preliminary study is aimed to explore how cancer cell metabolism in culture might recapitulate the metabolic alterations present in vivo...
2016: Scientific Reports
Daniele Oddo, Erin M Sennott, Ludovic Barault, Emanuele Valtorta, Sabrina Arena, Andrea Cassingena, Genny Filiciotto, Giulia Marzolla, Elena Elez, Robin M J M van Geel, Alice Bartolini, Giovanni Crisafulli, Valentina Boscaro, Jason T Godfrey, Michela Buscarino, Carlotta Cancelliere, Michael Linnebacher, Giorgio Corti, Mauro Truini, Giulia Siravegna, Julieta Grasselli, Margherita Gallicchio, René Bernards, Jan H M Schellens, Josep Tabernero, Jeffrey A Engelman, Andrea Sartore-Bianchi, Alberto Bardelli, Salvatore Siena, Ryan B Corcoran, Federica Di Nicolantonio
Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway...
August 1, 2016: Cancer Research
Deborah A Belchis, Li-Hui Tseng, Thomas Gniadek, Lisa Haley, Parvez Lokhandwala, Peter Illei, Christopher D Gocke, Patrick Forde, Julie Brahmer, Frederic B Askin, James R Eshleman, Ming-Tseh Lin
EGFR-mutated lung adenocarcinomas routinely develop resistance to tyrosine kinase inhibitors (TKI). To better characterize the relative frequencies of the resistance mechanisms, we analyzed 48 EGFR-mutated TKI-resistant specimens from 41 patients. Next-generation sequencing of post-treatment specimens detected EGFR p.T790M in 31 (79%) of 39 patients, PIK3CA mutations in 10 (26%), EGFR p.S768_V769delinsIL in one, and KRAS p.G12C in one. Five PIK3CA mutations were outside of codons 542, 545, and 1047. Three of four pre-treatment specimens did not carry the PIK3CA mutation found in the post-treatment sample...
July 19, 2016: Oncotarget
Elisa Caiola, Laura Brunelli, Mirko Marabese, Massimo Broggini, Monica Lupi, Roberta Pastorelli
KRAS mutations in non-small-cell lung cancer (NSCLC) patients are considered a negative predictive factor and indicate poor response to anticancer treatments. KRAS mutations lead to activation of the PI3K/akt/mTOR pathway, whose inhibition remains a challenging clinical target. Since the PI3K/akt/mTOR pathway and KRAS oncogene mutations all have roles in cancer cell metabolism, we investigated whether the activity of PI3K/akt/mTOR inhibitors (BEZ235 and BKM120) in cells harboring different KRAS status is related to their metabolic effect...
August 9, 2016: Oncotarget
Kwai Han Yoo, Nayoung K D Kim, Woo Il Kwon, Chung Lee, Sun Young Kim, Jiryeon Jang, Jungmi Ahn, Mihyun Kang, Hyojin Jang, Seung Tae Kim, Soomin Ahn, Kee-Taek Jang, Young Suk Park, Woong-Yang Park, Jeeyun Lee, Jin Seok Heo, Joon Oh Park
BACKGROUND: Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs. MATERIAL AND METHODS: Between January 2012 and June 2015, 40 BTC patients' samples were collected. PDCs were isolated and cultured from surgical specimens, biopsy tissues, or malignant effusions including ascites and pleural fluid...
June 2016: Translational Oncology
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