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KRAS, RAS

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https://www.readbyqxmd.com/read/28077300/pharmacological-strategies-to-target-oncogenic-kras-signaling-in-pancreatic-cancer
#1
REVIEW
Hsiao-Ching Chuang, Po-Hsien Huang, Samuel K Kulp, Ching-Shih Chen
The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents...
January 8, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28068936/retrospective-study-of-ras-pik3ca-braf-tumor-mutations-as-predictors-of-response-to-first-line-chemotherapy-with-bevacizumab-in-metastatic-colorectal-cancer-patients
#2
Izuma Nakayama, Eiji Shinozaki, Tomohiro Matsushima, Takeru Wakatsuki, Mariko Ogura, Takashi Ichimura, Masato Ozaka, Daisuke Takahari, Mitsukuni Suenaga, Keisho Chin, Nobuyuki Mizunuma, Kensei Yamaguchi
BACKGROUND: After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer...
January 9, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28050146/personalized-oncogenomics-in-the-management-of-gastrointestinal-carcinomas-early-experiences-from-a-pilot-study
#3
B S Sheffield, B Tessier-Cloutier, H Li-Chang, Y Shen, E Pleasance, K Kasaian, Y Li, S J M Jones, H J Lim, D J Renouf, D G Huntsman, S Yip, J Laskin, M Marra, D F Schaeffer
BACKGROUND: Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways. METHODS: We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma...
December 2016: Current Oncology
https://www.readbyqxmd.com/read/28032649/kras-mutation-coupled-with-p53-loss-is-sufficient-to-induce-ovarian-carcinosarcomas-in-mice
#4
Feng-Hsiang Tang, Tsung-Hua Hsieh, Chia-Yi Hsu, Hsiao-Yun Lin, Cheng-Yu Long, Kuang-Hung Cheng, Eing-Mei Tsai
Ovarian carcinosarcoma cancer is the most lethal form of gynecological malignancy, but the pathogenesis and biological function for this ovarian cancer remain unknown. We establishment the transgenic mouse model of K-ras(G12D) p53(loxP/loxP) and found that K-ras mutation and p53 deletion within the ovarian surface epithelium gave rise to ovarian lesions with a hyperproliferation and endometrioid glandular morphology. Furthermore, double mutant ovaries formed ovarian carcinosarcomas that were high grade and poorly differentiated...
December 29, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28031175/adjuvant-folfox-cetuximab-in-full-ras-and-braf-wildtype-stage-iii-colon-cancer-patients
#5
J Taieb, R Balogoun, K Le Malicot, J Tabernero, E Mini, G Folprecht, J-L Van Laethem, J-F Emile, C Mulot, S Fratté, C-B Levaché, L Saban-Roche, J Thaler, L N Petersen, J Bridgewater, G Perkins, C Lepage, E Van Cutsem, A Zaanan, P Laurent-Puig
BACKGROUND: RAS mutations have been shown to confer resistance to anti-EGFR treatment. We analyzed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. METHODS: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumors harboring RAS & BRAF WT and RAS mutations...
December 28, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28011498/metastatic-pattern-of-stage-iv-colorectal-cancer-with-high-frequency-microsatellite-instability-as-a-prognostic-factor
#6
Kenji Fujiyoshi, Gou Yamamoto, Takashi Takenoya, Akemi Takahashi, Yoshiko Arai, Mina Yamada, Miho Kakuta, Kensei Yamaguchi, Yoshito Akagi, Yoji Nishimura, Hirohiko Sakamoto, Kiwamu Akagi
BACKGROUND: A recent clinical trial on the immune check-point inhibitor pembrolizumab demonstrated that microsatellite instability (MSI) is a good biomarker for response to this inhibitor. However, clinicopathological features of advanced colorectal cancer (CRC) with high-frequency MSI (MSI-H) are unclear. PATIENTS AND METHODS: A total of 2,439 surgically resected CRC tissues were analyzed for MSI status, and mutational status of V-Ki-Ras2 Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS) and v-Raf murine sarcoma viral oncogene homolog B (BRAF)...
January 2017: Anticancer Research
https://www.readbyqxmd.com/read/28007785/p38mapk-builds-a-hyaluronan-cancer-niche-to-drive-lung-tumorigenesis
#7
Anna Brichkina, Thomas Bertero, Hui Mun Loh, Nguyet Thi Minh Nguyen, Alexander Emelyanov, Sidwell Rigade, Marius Ilie, Paul Hofman, Cedric Gaggioli, Dmitry V Bulavin
Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner...
December 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27999270/clinical-application-of-targeted-next-generation-sequencing-for-colorectal-cancers
#8
REVIEW
Quitterie Fontanges, Ricardo De Mendonca, Isabelle Salmon, Marie Le Mercier, Nicky D'Haene
Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority. For colorectal cancer (CRC) patients, international guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-epidermal growth factor receptor agents (anti-EGFR). Daily, new data emerge on the theranostic and prognostic role of molecular biomarkers, which is a strong incentive for a validated, sensitive and broadly available molecular screening test in order to implement and improve multi-modal therapy strategy and clinical trials...
December 16, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27999210/ly3009120-a-panraf-inhibitor-has-significant-anti-tumor-activity-in-braf-and-kras-mutant-preclinical-models-of-colorectal-cancer
#9
Eliza Vakana, Susan Pratt, Wayne Blosser, Michele Dowless, Nicholas Simpson, Xiu-Juan Yuan, Susan Jaken, Jason Manro, Jennifer Stephens, Youyan Zhang, Lysiane Huber, Sheng-Bin Peng, Louis F Stancato
Activating mutations in the KRAS and BRAF genes, leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade, are common in patients with colorectal cancer (CRC). While selective BRAF inhibitors are efficacious in BRAFmut melanoma, they have limited efficacy in BRAFmut CRC patients. In a RASmut background, selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity. A way to overcome such paradoxical activation is through concurrent inhibition of the kinase activity of both RAF isoforms...
December 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27994680/association-between-the-kras-gene-polymorphisms-and-papillary-thyroid-carcinoma-in-a-chinese-han-population
#10
Lifeng Ning, Wenwang Rao, Yaqin Yu, Xiaoli Liu, Yuchen Pan, Yuan Ma, Rui Liu, Shangchao Zhang, Hui Sun, Qiong Yu
Several studies have reported the association between MAPK signaling pathway gene polymorphisms and papillary thyroid carcinoma (PTC). KRAS gene, an oncogene from the mammalian RAS gene family plays an important role in the MAPK pathway. This study aimed to identify the potential association of KRAS gene polymorphisms with susceptibility to PTC in a Han Chinese population. A total of 861 patients with PTC, 562 disease controls with nodular goiter and 897 healthy controls were recruited. Four tagSNP polymorphisms (rs12427141, rs712, rs7315339 and rs7960917) of KRAS gene were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS)...
2016: Journal of Cancer
https://www.readbyqxmd.com/read/27992614/a-single-nucleotide-polymorphism-in-the-rasgrf2-gene-is-associated-with-alcoholic-liver-cirrhosis-in-men
#11
Ignacio Novo-Veleiro, Clara Cieza-Borrella, Isabel Pastor, Antonio-Javier Chamorro, Francisco-Javier Laso, Rogelio González-Sarmiento, Miguel Marcos
BACKGROUND: Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD)...
2016: PloS One
https://www.readbyqxmd.com/read/27991934/ras-oncogene-independent-activation-of-ralb-signaling-is-a-targetable-mechanism-of-escape-from-nras-v12-oncogene-addiction-in-acute-myeloid-leukemia
#12
E J Pomeroy, L A Lee, R D W Lee, D K Schirm, N A Temiz, J Ma, T A Gruber, E Diaz-Flores, B S Moriarity, J R Downing, K M Shannon, D A Largaespada, C E Eckfeldt
Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse...
December 19, 2016: Oncogene
https://www.readbyqxmd.com/read/27979926/crebbp-knockdown-enhances-ras-raf-mek-erk-signalling-in-ras-pathway-mutated-acute-lymphoblastic-leukaemia-but-does-not-modulate-chemotherapeutic-response
#13
Zach A Dixon, Lindsay Nicholson, Martin Zeppetzauer, Elizabeth Matheson, Paul Sinclair, Christine J Harrison, Julie A E Irving
Relapsed acute lymphoblastic leukaemia is the most common cause of cancer related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are particularly frequent in relapsed childhood acute lymphoblastic leukaemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukaemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukaemia cell lines and various primagraft acute lymphoblastic leukaemia cells...
December 15, 2016: Haematologica
https://www.readbyqxmd.com/read/27979717/perioperative-triplet-chemotherapy-and-cetuximab-in-patients-with-ras-wild-type-high-recurrence-risk-or-borderline-resectable-colorectal-cancer-liver-metastases
#14
Filippo Pietrantonio, Maria Di Bartolomeo, Christian Cotsoglou, Alessia Mennitto, Rosa Berenato, Federica Morano, Jorgelina Coppa, Federica Perrone, Roberto Iacovelli, Massimo Milione, Alessandra Alessi, Marta Vaiani, Ilaria Bossi, Francesca Ricchini, Mauro Scotti, Marta Caporale, Emilio Bajetta, Filippo de Braud, Vincenzo Mazzaferro
BACKGROUND: For borderline resectable colorectal cancer liver metastases (CLM), systemic treatment can help to achieve R0 resection and reduce the risk of relapse. We assessed the role of perioperative triplet chemotherapy in combination with cetuximab in patients with RAS wild type high recurrence risk and/or borderline resectable CLM. PATIENTS AND METHODS: This was a monocenter, open-label phase II study. Borderline resectability was defined technically as tumor involvement of >1 hepatic vein, or >4 hepatic segments, need for 2-stage hepatectomy or radiofrequency ablation, and/or biologically (high risk): ≥4 metastatic nodules, or synchronous metastases...
October 6, 2016: Clinical Colorectal Cancer
https://www.readbyqxmd.com/read/27974679/kras-mutation-analysis-of-washing-fluid-from-endoscopic-ultrasound-guided-fine-needle-aspiration-improves-cytologic-diagnosis-of-pancreatic-ductal-adenocarcinoma
#15
Joo Kyung Park, Yoon Jung Lee, Jong Kyun Lee, Kyu Taek Lee, Yoon-La Choi, Kwang Hyuck Lee
EUS-FNA becomes one of the most important diagnostic modalities for PDACs. However, acquired tissue specimens were sometimes insufficient to make a definite cytological diagnosis. On the other hand, KRAS mutation is the most frequently acquired genetic alteration found more than 90% of PDACs. To investigate the way to improve diagnostic accuracy for PDACs using both cytological examination and KRAS mutation analysis would be a great help. Therefore, the aims of this study were to evaluate usefulness of conventional cytological examination combined with KRAS mutation analysis with modified PCR technology to improve the sensitivity and the accuracy...
December 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27974047/fgfr1-and-ntrk3-actionable-alterations-in-wild-type-gastrointestinal-stromal-tumors
#16
Eileen Shi, Juliann Chmielecki, Chih-Min Tang, Kai Wang, Michael C Heinrich, Guhyun Kang, Christopher L Corless, David Hong, Katherine E Fero, James D Murphy, Paul T Fanta, Siraj M Ali, Martina De Siena, Adam M Burgoyne, Sujana Movva, Lisa Madlensky, Gregory M Heestand, Jonathan C Trent, Razelle Kurzrock, Deborah Morosini, Jeffrey S Ross, Olivier Harismendy, Jason K Sicklick
BACKGROUND: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies. METHODS: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations...
December 14, 2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27941888/cib1-contributes-to-oncogenic-signalling-by-ras-via-modulating-the-subcellular-localisation-of-sphingosine-kinase-1
#17
W Zhu, B L Gliddon, K E Jarman, P A B Moretti, T Tin, L V Parise, J M Woodcock, J A Powell, A Ruszkiewicz, M R Pitman, S M Pitson
CIB1 (calcium and integrin binding protein 1) is a small intracellular protein with numerous interacting partners, and hence has been implicated in various cellular functions. Recent studies have revealed emerging roles of CIB1 in regulating cancer cell survival and angiogenesis, although the mechanisms involved have remained largely undefined. In investigating the oncogenic function of CIB1, we initially found that CIB1 is widely up-regulated across a diverse range of cancers, with this upregulation frequently correlating with oncogenic mutations of KRas...
December 12, 2016: Oncogene
https://www.readbyqxmd.com/read/27936234/cell-density-dependent-increase-in-tyrosine-monophosphorylated-erk2-in-mdck-cells-expressing-active-ras-or-raf
#18
Noriyuki Kawabata, Michiyuki Matsuda
The extracellular signal-regulated kinase (ERK) is one of the principal hub proteins that transmit growth signals from upstream oncogene products including Ras and BRaf to downstream effector proteins. However, there are both reports supporting and refuting the increase in ERK activity in cancer tissues expressing the active Ras and BRaf proteins. We considered that the cell density might account for this discrepancy. To examine this possibility, we prepared Madin-Darby canine kidney (MDCK) cells that expressed an active HRas, NRas, KRas, or BRaf and an ERK biosensor based on the principle of Förster resonance energy transfer (FRET)...
2016: PloS One
https://www.readbyqxmd.com/read/27936046/the-ras-effector-interface-isoform-specific-differences-in-the-effector-binding-regions
#19
Hossein Nakhaeizadeh, Ehsan Amin, Saeideh Nakhaei-Rad, Radovan Dvorsky, Mohammad Reza Ahmadian
RAS effectors specifically interact with the GTP-bound form of RAS in response to extracellular signals and link them to downstream signaling pathways. The molecular nature of effector interaction by RAS is well-studied but yet still incompletely understood in a comprehensive and systematic way. Here, structure-function relationships in the interaction between different RAS proteins and various effectors were investigated in detail by combining our in vitro data with in silico data. Equilibrium dissociation constants were determined for the binding of HRAS, KRAS, NRAS, RRAS1 and RRAS2 to both the RAS binding (RB) domain of CRAF and PI3Kα, and the RAS association (RA) domain of RASSF5, RALGDS and PLCε, respectively, using fluorescence polarization...
2016: PloS One
https://www.readbyqxmd.com/read/27935847/structure-based-development-of-pde%C3%AE-inhibitors
#20
Pablo Martín-Gago, Eyad Kalawy Fansa, Alfred Wittinghofer, Herbert Waldmann
The prenyl binding protein PDEδ enhances the diffusion of farnesylated Ras proteins in the cytosol, ultimately affecting their correct localization and signaling. This has turned PDEδ into a promising target to prevent oncogenic KRas signaling. In this review we summarize and describe the structure-guided-development of the three different PDEδ inhibitor chemotypes that have been documented so far. We also compare both their potency for binding to the PDEδ pocket and their in vivo efficiency in suppressing oncogenic KRas signaling, as a result of the inhibition of the PDEδ/KRas interaction...
December 21, 2016: Biological Chemistry
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