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PubMed Journals Articles About "Mirati Details Early Results KRAS Inhibitor MRTX849 Http" RSS

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Showing "Mirati details early results KRAS inhibitor MRTX849 http" PubMed Articles 1–25 of 48,000+

STAT3 inhibitor sensitized KRAS-mutant lung cancers to RAF inhibitor by activating MEK/ERK signaling pathway.

KRAS is frequently mutated in patients with lung cancers, resulting in low survival rates. Inhibiting the downstream pathways of KRAS seems to be a feasible strategy to target KRAS-mutant tumors. However, the clinical outcomes only show limited success. Here, we developed a novel strategy by combining RAF (AZ628) and STAT3 (BP-1-102) inhibitors. The results showed that the AZ628 and BP-1-102 combination showed strongly synergistic effects on KRAS(G12D) H838, KRAS(G12S) H292 and KRAS(G12V) H441 cells and sig...


Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator.

No effective approaches to target mutant Kras have yet been developed. Immunoprevention using KRAS-specific antigenic peptides to trigger T cells capable of targeting tumor cells relies heavily on lipid metabolism. To facilitate better TCR/peptide/MHC interactions that result in better cancer preventive efficacy, we combined KVax with avasimibe, a specific ACAT1 inhibitor, tested their anti-cancer efficacy in mouse lung cancer models, where Kras mutation was induced before vaccination.

Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer.

KRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK.


Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D.

Ras GTPases are mutated at codons 12, 13, and 61, with different frequencies in KRas, HRas, and NRas and in a cancer-specific manner. The G13D mutant appears in 25% of KRas-driven colorectal cancers, while observed only rarely in HRas or NRas. Structures of Ras G13D in the three isoforms show an open active site, with adjustments to the D13 backbone torsion angles and with disconnected switch regions. KRas G13D has unique features that destabilize the nucleotide-binding pocket. In KRas G13D bound to GDP, A5...

Targeting Mutant KRAS for Anticancer Therapy.

Over the past decades, designing therapeutic strategies to target KRAS-mutant cancers, which is one of the most frequent mutant oncogenes among all cancer types, have proven unsuccessful regardless of many concerted attempts. There are key challenges for KRAS-mutant anticancer therapy, as the complex cellular processes involved in KRAS signaling has present. Herein we highlight the emerging therapeutic approaches for inhibiting KRAS signaling and blocking KRAS functions, in hope to serve as a more effective...

Mu-KRAS attenuates Hippo signaling pathway through PKCι to sustain the growth of pancreatic cancer.

The atypical protein kinase C isoform ι (PKCι) is upregulated, which cooperates with mutated KRAS (mu-KRAS) to promote the development of pancreatic cancers. However, the exact role of PKCι in KRAS-mediated pancreatic tumorigenesis is not fully defined. In the present study, we demonstrate that mu-KRAS upregulates and activates PKCι, accompanied by dephosphorylation of large tumor suppressor (LATS), a key member of the growth-inhibiting Hippo signaling pathway. As a result, Yes-associated protein 1 (YAP...

MicroRNA-425-5p Expression Affects BRAF/RAS/MAPK Pathways In Colorectal Cancers.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide and about 20% is metastatic at diagnosis and untreatable. The anti-EGFR therapy in metastatic patients is led by the presence of KRAS-mutations in tumor tissue. KRAS-wild-type CRC patients showed a positive response rate of about 70% to cetuximab or panitumumab combined with chemotherapy. MiRNAs are promising markers in oncology and could improve our knowledge on pathogenesis and drug resistance in CRC patients. This class of molecules rep...

The ROS-KRAS-Nrf2 axis in the control of the redox homeostasis and the intersection with survival-apoptosis pathways: Implications for photodynamic therapy.

In highly proliferating cancer cells oncogenic mutations reprogram the metabolism and increase the production of reactive oxygen species (ROS). Cancer cells prevent ROS accumulation by upregulating antioxidant systems. Here we show that an increase of oxidative stress (ROS and singlet oxygen), generated by photoactivated TMPyP4, results in the upregulation of KRAS and Nrf2, the major regulator of the redox homeostasis. In agreement with a previous observation, the ectopic expression of KRAS G12D or G12 V ...

Detection of mutations in circulating cell-free DNA in relation to disease stage in colorectal cancer.

Enthusiasm has emerged for the potential of liquid biopsies to provide easily accessible genetic biomarkers for early diagnosis and mutational cancer characterization. We here systematically investigated the suitability of circulating cell-free DNA (cfDNA) analysis for mutation detection in colorectal cancer (CRC) patients with respect to clinicopathological disease stage. Droplet Digital PCR (ddPCR) was performed to detect common point mutations in the KRAS and BRAF oncogenes in cfDNA from 65 patients and ...

Curcumin functions as a MEK inhibitor to induce a synthetic lethal effect on KRAS mutant colorectal cancer cells receiving targeted drug regorafenib.

Curcumin, a major yellow pigment and spice in turmeric and curry, has been demonstrated to have an anticancer effect in human clinical trials. Mutation of KRAS has been shown in 35%-45% of colorectal cancer, and regorafenib has been approved by the US FDA to treat patients with colorectal cancer. Synthetic lethality is a type of genetic interaction between two genes such that simultaneous perturbations of the two genes result in cell death or a dramatic decrease of cell viability, while a perturbation of ei...

High-throughput single-particle tracking reveals nested membrane domains that dictate KRas diffusion and trafficking.

Membrane nanodomains have been implicated in Ras signaling, but what these domains are and how they interact with Ras remain obscure. Here, using single particle tracking with photoactivated localization microscopy (spt-PALM) and detailed trajectory analysis, we show that distinct membrane domains dictate KRas (an active KRas mutant) diffusion and trafficking in U2OS cells. KRas exhibits an immobile state in ~70 nm domains, each embedded in a larger domain (~200 nm) that confers intermediate mobility, while...

Activating KRAS mutations in arteriovenous malformations of the brain: frequency and Clinicopathologic correlation.

Arteriovenous malformations (AVM) of the brain are considered congenital. Most AVMs are presumably sporadic, however rare familial cases occur and they may be observed in certain genetic disorders. We sought to determine the frequency of KRAS mutations and their association with clinicopathologic characteristics. We searched our neuropathology database from 2014-2017 for resected AVMs of the brain or dura mater. Twenty-one AVMs were tested (12 females, 9 males; average age: 32years). KRAS mutations were fou...

Drug Combinatorial Therapies for Treatment of KRAS Mutated Lung Cancers.

KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS has proven to be challenging. The mutations of KRAS are associated with poor prognosis, resistance to both adjuvant therapy and targeted EGFR TKI. The EGFR TKI provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to EGFR TKI therapy. Thus, the combination therapy is essential for the treatment of lung cancers with KRAS mutat...

KRAS mutations in tongue squamous cell carcinoma.

p16 (p16) expression in tongue cancer (TC) is reportedly not associated with human papilloma virus (HPV). Mutations of KRAS in cancer cells are most frequently observed within codon 12. However, few reports have investigated the association between KRAS mutations and p16 status in TC.

Progression of liver tumor was promoted by tris(1,3-dichloro-2-propyl) phosphate through the induction of inflammatory responses in kras transgenic zebrafish.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been detected in various environmental media and has been implicated as a weak mutagen or carcinogen, but whether TDCIPP can promote the progression of liver tumor remains unclear. In this study, kras genetically modified zebrafish, Tg(fabp10:rtTA2s-M2; TRE2:EGFP-kras), a model system in which liver tumors can be induced by doxycycline (DOX), was used to evaluate the liver tumor promotion potential of TDCIPP. Briefly, kras transgenic females were exposed to...

Differential cell susceptibilities to Kras in the setting of obstructive chronic pancreatitis.

Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC) but how it synergizes with KRAS mutation is not known.

Interrogator intonation and memory encoding performance.

Based on recent findings that interrogator intonation can enhance interrogative suggestibility during recall phases, the present study tested influences of interrogator intonation on memory performance even as early as at the encoding stage. We experimentally manipulated interrogator intonation during encoding of a story to be recalled in immediate and delayed subsequent memory tests (Experiment 1, N = 50). As expected, a symmetrically structuring vs. an isolating-emphasizing speaking style generally increa...

A Chirality-Dependent Action of Vitamin C in Suppressing KRAS Mutant Tumor Growth by the Oxidative Combination: Rationale for Cancer Therapeutics.

Kirsten rat sarcoma (KRAS) mutant cancers, which constitute the vast majority of pancreatic tumors, are characterized by their resistance to established therapies and high mortality rates. Here, we developed a novel and extremely effective combinational therapeutic approach to target KRAS mutant tumors through the generation of a cytotoxic oxidative stress. At high concentrations, Vitamin C (VC) is known to provoke oxidative stress and selectively kill KRAS mutant cancer cells, although its effects are limi...

Downregulation of Notch Signaling in Kras-Induced Gastric Metaplasia.

Activating mutations and amplification of Kras and, more frequently, signatures for Kras activation are noted in stomach cancer. Expression of mutant Kras in the mouse gastric mucosa has been shown to induce hyperplasia and metaplasia. However, the mechanisms by which Kras activation leads to gastric metaplasia are not fully understood. Here we report that Kras;Pdx1-cre, a mouse model known for pancreatic cancer, also mediates Kras expression in the stomach, causing gastric hyperplasia and metaplasia prior ...

Proteogenomic Network Analysis of Context-Specific KRAS Signaling in Mouse-to-Human Cross-Species Translation.

The highest frequencies of KRAS mutations occur in colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC). The ability to target downstream pathways mediating KRAS oncogenicity is limited by an incomplete understanding of the contextual cues modulating the signaling output of activated K-RAS. We performed mass spectrometry on mouse tissues expressing wild-type or mutant Kras to determine how tissue context and genetic background modulate oncogenic signaling. Mutant Kras dramatically altered ...

Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis.

The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis.

Comparison of PANAMutyper and PNAClamp for Detecting KRAS Mutations from Patients With Malignant Pleural Effusion.

KRAS is one of the frequently mutated genes in human cancers and often relates with drug resistance and poor prognosis. PANAMutyper™ is a novel technology that integrates PNAClamp™ and PANA S-Melting™. In the present study, PANAMutyper™ and PNAClamp™ were compared for the detection of KRAS mutations using different samples of patients with malignant pleural effusion.

Concentrations of trace elements and KRAS mutations in pancreatic ductal adenocarcinoma.

Trace elements are a possible risk factor for pancreatic ductal adenocarcinoma (PDAC). However, their role in the occurrence and persistence of KRAS mutations remains unstudied. There appear to be no studies analyzing biomarkers of trace elements and KRAS mutations in any human cancer. We aimed to determine whether patients with KRAS mutated and non-mutated tumours exhibit differences in concentrations of trace elements. Incident cases of PDAC were prospectively identified in five hospitals in Spain. KRAS m...

Dual-targeting of EGFR and Neuropilin-1 Attenuates Resistance to EGFR-targeted Antibody Therapy in KRAS-mutant Non-Small Cell Lung Cancer.

The therapeutic targeting of oncogenic KRAS mutant-harboring (KRAS) non-small cell lung cancer (NSCLC) is an urgent unmet need in cancer therapy. Although NSCLC is often driven by epidermal growth factor receptor (EGFR) overexpression and/or mutations, no EGFR-targeted therapy is clinically available for KRAS NSCLC. In this study, we show that integrin β3 expression is associated with the intrinsic resistance of KRAS NSCLCs to the anti-EGFR antibody cetuximab. Further analyses identified an integrin β3-me...

Risk factors for wheezing in primary health care settings in the tropics.

The "International Study of Wheezing in Infants (EISL)", is a cross-sectional, population-based study, based on ISAAC. "(Http // www.isaac.auckland.ac.nz). It uses a validated questionnaire on early wheezing and risk/protective factors.


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