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Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer

Abstract BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1,2,3.

Nature 19h ago

Molecular basis of competence for neural induction in the chick embryo

Competence is the capacity of a cell or tissue to respond to a specific inducing signal from a neighbouring tissue, by changing its fate in a specific direction. Neural induction is the process by which the epiblast of the early embryo responds to signals from the organizer (the tip of the primitive streak in amniotes) by forming a neural plate. Here we study why three regions of the early chick embryo lack competence to respond to neural induction by a grafted organizer: the outer anterior...

bioRxiv 4d ago

Radiosensitization of Glioblastoma by the K-ras Inhibitor RMC-6236

Purpose: Glioblastoma (GBM) is characterized by poor clinical outcomes and marked resistance to radiotherapy. Because effective radiosensitizing strategies for GBM remain limited, we investigated whether inhibition of KRAS/RAS signaling could enhance radiation response in GBM. In particular, we evaluated the radiosensitizing potential of RMC-6236, an RAS(ON) multiselective inhibitor that suppresses active RAS signaling across multiple RAS-dependent states.

bioRxiv 8d ago

O-GlcNAc transferase regulates H2O2 production via p38 MAPK

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by augmented transforming growth factor-{beta} (TGF-{beta}) signaling leading to excessive extracellular matrix (ECM) deposition. The fibroblast-to-myofibroblast-transition (FMT) and metabolic reprogramming of lung fibroblasts (HLFs) are essential to IPF pathogenesis, yet the connection between nutrient metabolism and fibrogenesis remains poorly defined. The O-linked N-acetylglucosamine (O-GlcNAc)...

bioRxiv 10d ago

Effects of ERK1/2 Signaling on Cell Cycle Regulation by the Tuberin-Cyclin B1 Complex

How cells balance growth (cell size) and division (cell number) requires a complex interplay between response to external signals, including growth factors, nutrient availability and metabolic cues, along with regulation of the cell cycle. The protein Tuberin (gene TSC2) is a critical regulator of these decisions. In a complex with the protein Hamartin, Tuberin functions as a negative regulator of the Target of Rapamycin (mTOR) pathway, preventing excessive growth under unfavorable conditions.

bioRxiv 3d ago