Jawahar Sudhamsu

Abstract Leucine-rich-repeat-containing protein 15 (LRRC15) is selectively expressed on cancer-associated fibroblasts (CAFs) and constitutes a promising biomarker for imaging the tumor microenvironment. Using a combinatorial library approach, assisted by machine learning, we developed disulfide-constrained peptides (DCPs), notably ML-YSD-07 and ML-PD-03, that demonstrate subnanomolar affinities for murine LRRC15 (muLRRC15) and specifically localize onto muLRRC15-expressing fibroblasts.

Abstract The RAS–RAF pathway is one of the most commonly dysregulated in human cancers1,2,3. Despite decades of study, understanding of the molecular mechanisms underlying dimerization and activation4 of the kinase RAF remains limited. Recent structures of inactive RAF monomer5 and active RAF dimer5,6,7,8 bound to 14-3-39,10 have revealed the mechanisms by which 14-3-3 stabilizes both RAF conformations via specific phosphoserine residues.

Highlights • CRAF depletion inhibits tumor growth but not ERK signaling in KRAS mutant cells • CRAF kinase domain dimerization and not kinase activity is essential for tumorigenesis • Quantitative proteomics reveal increased levels of CRAF:ARAF versus CRAF:BRAF dimers • ARAF dimers promote ERK signaling upon CRAF loss, leading to cell-cycle arrest Summary KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade.