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:
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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/

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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

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- NF1 loss increases Ras-GTP and pERK, promoting proliferation
- NF1 loss decreases sensitivity to MEK inhibitors via altered feedback
- PTPN11 (SHP2) perturbation reduces Ras activity and sensitizes to MEK inhibition
- SOS1 inhibition is limited by SOS2 compensation; SOS2 knockdown improves SOS1 inhibition response
- KRAS, not HRAS/NRAS, is enriched near neurofibromin; KRAS repression increases selumetinib sensitivity
- Pan-KRAS inhibitor BI-2865 suppresses ERK activation and CDK1/2 in NF1 mutant cells

QC result: Pass.