Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF-Mutant Human Glioma.

Purpose: Selective RAF-targeted therapy is effective in some patients with BRAF-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms.

Experimental Design: Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples ( = 15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing (RNA-seq). Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAF-mutant glioma cell lines.

Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma.

Background: RAS effector signaling pathways such as PI3K/mTOR and ERK are frequently dysregulated in glioblastoma. While small molecule targeted therapies against these pathways have appeared promising in preclinical studies, they have been disappointing in clinical trials due to toxicity and de novo and adaptive resistance. To identify predictors of glioblastoma sensitivity to dual pathway inhibition with mTORC1/2 and MEK inhibitors, we tested these agents, alone and in combination, in a cohort of genomically characterized glioblastoma cell lines.

Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors.

Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival.

A Secondary Mutation in Confers Resistance to RAF Inhibition in a -Mutant Brain Tumor.

BRAF hyperactivates ERK and signals as a RAF inhibitor-sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a -mutant brain tumor treated with dabrafenib.

A role for mammalian target of rapamycin in regulating T cell activation versus anergy.

Whether TCR engagement leads to activation or tolerance is determined by the concomitant delivery of multiple accessory signals, cytokines, and environmental cues. In this study, we demonstrate that the mammalian target of rapamycin (mTOR) integrates these signals and determines the outcome of TCR engagement with regard to activation or anergy. In vitro, Ag recognition in the setting of mTOR activation leads to full immune responses, whereas recognition in the setting of mTOR inhibition results in anergy.