Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma
Background: Loss of function in neurofibromin (NF1) is a frequent alteration in cancer, found in up to 20% of melanomas (MSKCC Clinical Sequencing Cohort). Unlike BRAF V600E melanoma, no effective targeted therapies currently exist for NF1-null melanoma patients if they fail or cannot tolerate immunotherapy. NF1 acts as a negative regulator of RAS-ERK signaling; therefore, mutations that impair NF1 activity lead to ERK overactivation, which drives tumor growth. Due to their higher ERK activity, NF1-null melanoma cells should be sensitive to MEK inhibition; still, clinical data suggest that these patients rarely derive durable benefit from treatment with MEK inhibitors.
Authors
- Daniel Gerlach (ORCID: https://orcid.org/0000-0001-9338-3765)
- Jianfeng Qiu (ORCID: https://orcid.org/0000-0002-8049-3743)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Zhan Yao (ORCID: https://orcid.org/0000-0001-5391-5691)
- Sandra Misale (ORCID: https://orcid.org/0000-0002-6031-0137)
- Soren Cole
- Jedd Wolchok
- T. Merghoub
- Andrea Bähr (ORCID: https://orcid.org/0000-0001-8075-8222)
- Michelangelo Marasco (ORCID: https://orcid.org/0000-0001-7082-9824)
- Salud Borrego (ORCID: https://orcid.org/0000-0002-2513-6161)
- Marco H. Hofmann (ORCID: https://orcid.org/0000-0001-7557-1156)
- Esther Kaplun (ORCID: https://orcid.org/0000-0002-3879-020X)
- Fabio Savarese
- Ilinca Aricescu
- Besnik Qeriqi (ORCID: https://orcid.org/0000-0001-8327-1081)
- Thomas W. Seale
- D. Solit
- Deborah Fidele
- Darshan Kumar (ORCID: https://orcid.org/0000-0001-5371-1779)
- Chen Xu (ORCID: https://orcid.org/0000-0003-3477-2204)
- N. Rosen
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Memorial Sloan Kettering Cancer Center (US)
- Johns Hopkins University (US)
- Cornell University (US)
- Johns Hopkins Medicine (US)
- Boehringer Ingelheim (Austria) (AT)
- Loxo Oncology at Lilly (United States) (US)
Publication Details
- Journal
- EJC Skin Cancer
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.ejcskn.2025.100470
- Citations
- 1
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.81