refametinib (BAY86-9766)

In addition, the high expression of model gene produced drug resistance to trametinib, selumetinib and RDEA119 (refametinib). The prognostic risk model based on six prognostic related DEGs is an independent prognostic factor of HCC, which can effectively predict the survival and prognosis of HCC patients.

CPNE1 could be a predictive biomarker and a potential target for biological therapy in STAD.

Overall, our results describe the importance of Twist1 in MPNST pathogenesis. Everolimus was also found to be a potential therapeutic drug for MPNSTs.

The results suggest that the sensitivity toward trametinib, refametinib (RDEA119), and selumetinib correlates to the expression of WDR76. ROC analysis showed that the area under the curve (AUC) of all genes in the regulatory axis was greater than 0.7. The identified hsa_circ_0000417/hsa_circ_0002688/hsa_circ_0001387--hsa-miR-199a-5p--WDR76 regulatory axis may provide new insights into the progression, clinical diagnosis, and treatment of HCC.

Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer.

High expression of HIST1H1E was resistant to trametinib, selumetinib, RDEA119, docetaxel and 17-AAG, High expression of UBE2C was resistant to masitinib, and Low expression of ERO1B made the EC more sensitive to FK866. We constructed an EC risk score model composed of 8 DEGs and gene resistance analysis, which can provide reference for prognosis prediction, diagnosis and treatment of the EC patients.

Finally, we suggested KGs-guided three repurposable candidate-drugs (Trametinib, selumetinib, and RDEA119) for BC treatment by using the GSCALite online web tool and validated them through molecular docking analysis, and found their strong binding affinities. Therefore, the findings of this study might be useful resources for BC diagnosis, prognosis and therapies.

Combined treatment of AZD8055 with the MAPK kinase1/2 (MEK1/2) inhibitor refametinib or the p38 inhibitor SB203580 markedly decreased translation in HepG2 cells. Interestingly, AZD8055 modulated the 4E-BP1 mRNA pool by up-regulating ERK1/2 and p38 pathways. Together, these results suggest that AZD8055-induced activation of MAPKs interferes with inhibition of protein synthesis at an early stage of mTORC1/2 inhibition, and that it may contribute to the development of resistance to mTORC1/2 inhibitors.

PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

Application of the allosterically acting MEK inhibitors (MEKi) trametinib, cobimentinib, refametinib, and selumetinib converted activated MEK1 KinCon reporters back into a more closed inactive conformation. We observed increased dynamics for the S218D/S222D double mutant particularly in the region of the distal A-helix and alpha-C helix. These data underline that MEK1 KinCon biosensors have the potential to be subjected to MEKi efficacy validations in an intact cell setting.

Mouse PDAC models and human PDAC cell lines as well as human PDAC xenografts treated with the MEK inhibitor trametinib or refametinib led to an enhanced expression of lysosomal markers and enrichment of lysosomal gene sets. Therefore, MEK inhibition triggers lysosomal biogenesis and subsequent drug sequestration. Combined targeting of MEK and lysosomal function may improve sensitivity to MEK inhibition in PDAC.

Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identified for this drug combination that was both tolerable and offered clear efficacy in the population assessed. CLINICALTRIALS.

Mouse PDAC models and human PDAC cell lines as well as human PDAC xenografts treated with the MEK inhibitor trametinib or refametinib led to an enhanced expression of lysosomal markers and enrichment of lysosomal gene sets. Therefore, MEK inhibition triggers lysosomal biogenesis and subsequent drug sequestration. Combined targeting of MEK and lysosomal function may improve sensitivity to MEK inhibition in PDAC.