115: Neurofibromin, KRAS, and new targets for NF1 tumors

Vasudevan HN et al., PNAS - CRISPRi, transcriptomic and proteomic profiling in peripheral nervous system cell models reveal how NF1 loss rewires Ras signaling, alters MEK inhibitor response, and nominates KRAS as a direct neurofibromin effector and therapeutic target. Key terms: neurofibromin, NF1 loss, KRAS, MEK inhibitor, SHP2 SOS2 compensation. Study Highlights:Repressing NF1 in immortalized peripheral nerve (iPN) cells increases Ras‑GTP and pERK, drives proliferation and dedifferentiation, and reduces biochemical sensitivity to the MEK inhibitor selumetinib through altered feedback. CRISPRi of PTPN11 produces the opposite transcriptomic program, lowers Ras activity, and sensitizes cells to selumetinib, while SOS1 inhibition is limited by SOS2 compensation. APEX proximity proteomics shows neurofibromin preferentially associates with KRAS (not HRAS/NRAS) in PNS cells, and pan‑KRAS inhibition suppresses ERK and CDK1/2 activity in NF1 mutant cells. Together these data map upstream inputs and downstream outputs of Ras after NF1 loss and identify KRAS as a key, druggable effector in PNS models. Conclusion:Systematic genetic, transcriptomic, and proteomic dissection in PNS cell models indicates NF1 loss drives KRAS-dependent RAF/MEK/ERK activation and altered MEK inhibitor feedback; targeting KRAS directly — or upstream SHP2 rather than SOS1 where SOS2 compensates — may offer improved therapeutic strategies for NF1-mutant peripheral nerve tumors. Music:Enjoy the music based on this article at the end of the episode. Article title:A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system First author:Vasudevan HN Journal:PNAS DOI:10.1073/pnas.2506823122 Reference:Vasudevan HN, Arang N, Sacconi Nunez M, Kennedy P, Payne E, Mohabeer S, Chien J, Wright A, Sale MJ, Kroganc NJ, Forget A, McCormick F. A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system. Proc Natl Acad Sci U S A. 2025;122(27):e2506823122. doi:10.1073/pnas.2506823122 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/a-transcriptomic-proteomic-and-functional-genetic-atlas-dissects-neurofibromin-function-in-the-peripheral-nervous-system QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-24. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing NF1 loss, Ras signaling, MEK inhibitor resistance, upstream inputs (SOS1/SOS2, SHP2/PTPN11), KRAS as the neurofibromin effector, proximity labeling results, pan-KRAS inhibition, and clinical/translational implications.- transcript topics: NF1 loss and Ras signaling in peripheral nervous system cells; MEK inhibitor resistance and feedback rewiring; Upstream Ras inputs: SOS1/SOS2 and SHP2 (PTPN11); SHP2 vs SOS1 inhibition and compensation by SOS2; APEX proximity labeling: KRAS as the NF1 effector; Pan-KRAS inhibition (BI-2865) effects on ERK and CDK1/2 QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0<... Chapters (00:00:00) - Finding a cure for cancer with no cure(00:01:36) - PNAS Live: NF1-related neurofibromat(00:04:39) - How did they systematically break down neurofiberman's function?(00:05:28) - How did they find NF1 deficiency in neurofibromin(00:06:50) - NF1 deficiency in advanced neurofibromas(00:09:32) - Kras as the key player in NF1 cancer therapy