Fig 2: A proposed model for knockdown of astrocytic Grin2a aggravated Aß-induced synaptotoxicity. The reduced astrocytic GluN2A can counteract Aß-induced compensatory protective increase of ß-NGF through modulating pNF-?B, Furin and VAMP3, which modulating the synthesis, mature and secretion of NGF respectively

Fig 3: SNARE interactions with KRAS are selectively SNORD50A/B-dependent. a Proximity ligation analysis (PLA) between KRAS and either SNAP23, SNAP29, or VAMP3, as well as single antibody controls in H23. Significance of WT cells determined by comparison to single antibody controls while significance of KO cells determined by comparison to WT. b Schematic of KRAS mutants used in proximity protein labeling experiments. c Strength of interaction between Raf1, SNAP23, SNAP29, or VAMP3 with KRAS mutants measured by proximity protein labeling followed by pulldown western blotting (n = 2) in H23. d Quantitation of c. e Interaction strength of Raf1 and SNAREs with KRASWT and KRASG13D in H23. f Quantification of e (n = 2). g Localization of HA-tagged KRAS and endogenous SNAP23, SNAP29, and VAMP3 visualized by super-resolution microscopy in A549. Scale bars are 5 µm. h Co-immunoprecipitation of endogenous RAS and SNARE proteins from A549 lysate. i Far western blot with spotted purified recombinant protein indicated by row name. Bound recombinant KRAS was detected with an anti-RAS antibody. Coomassie stain for total protein loading (middle) (n = 3, representative images shown). j Quantification of i. Error bars are s.e.m

Fig 4: SNAP23 is a potentially targetable vulnerability of KRAS. a Schematic of a focused co-essentiality CRISPR screen targeting KRAS, HRAS, NRAS, SNAP23, SNAP29, and VAMP3 (n = 14 tumors). b Correlation of in vivo tumorigenesis sgRNA counts by target gene in CRISPR screen. c Growth in culture of H23 expressing BoNT light chain E (LC/E) and LC/EK224D (n = 2). d Tumor volumes of H23 expressing BoNT light chain E (LC/E) and LC/EK224D at day 16 (n = 10 tumors per condition). Error bars are s.e.m

Fig 5: SNARE-enabled transport is a vulnerability of KRAS-driven cancer. a Survival of KRAS-mutant pancreatic adenocarcinoma patients depending on mutation and expression status of SNAP23 and VAMP3 (n = 186). b Survival of KRAS-mutant pancreatic adenocarcinoma patients depending on mutation and expression status of the 36 other SNARE proteins (n = 162). c Subcutaneous in vivo tumor growth of H23 SHO immune deficient mice (n = 4 mice/group). d Immunofluorescence images of phosphorylated and total AKT in oncogenic KRAS-driven DLD-1 subcutaneous tumors. e Immunofluorescence images of phosphorylated and total ERK in oncogenic KRAS-driven DLD-1 subcutaneous tumors. f Quantitation of d and e. g Subcutaneous in vivo tumor growth in DLD-1 isogenic lines (n = 4 mice/group). Error bars are s.e.m