Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma Journal Article
| Authors: | Marasco, M.; Kumar, D.; Seale, T.; Borrego, S. G.; Kaplun, E.; Aricescu, I.; Cole, S.; Qeriqi, B.; Qiu, J.; Chen, X.; Bahr, A.; Fidele, D.; Hofmann, M. H.; Gerlach, D.; Savarese, F.; Merghoub, T.; Wolchok, J. D.; Yao, Z.; de Stanchina, E.; Solit, D.; Misale, S.; Rosen, N. |
| Article Title: | Concurrent SOS1 and MEK suppression inhibits signaling and growth of NF1-null melanoma |
| Abstract: | Neurofibromin (NF1) is a negative regulator of RAS signaling, frequently mutated in cancer. NF1-mutant melanoma is a highly malignant tumor for which targeted therapies are lacking. Here, we use biochemical and pharmacological assays on patient-derived models and isogenic cell lines to identify potential pharmacologic targets, revealing that NF1-null melanomas are dependent on RAS activation and that MEK inhibition relieves ERK-dependent negative feedback, increasing RAS signaling. MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited. However, concurrent inhibition of MEK and SOS1 abrogates ERK activation, induces cell death, and suppresses tumor growth. In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells. © 2024 The Author(s) |
| Keywords: | controlled study; protein phosphorylation; human cell; nonhuman; cell proliferation; animal cell; mouse; phenotype; cell death; cell viability; melanoma; apoptosis; gene expression; tumor volume; animal experiment; animal model; western blotting; neurofibromin; guanosine triphosphatase activating protein; real time polymerase chain reaction; tumor growth; combination therapy; depletion; nf1; diagnostic test accuracy study; mek inhibition; mitogen activated protein kinase kinase inhibitor; trametinib; mapk signaling; human; article; sos protein; malignant neoplasm; pull-down assay; avutometinib; sos1 inhibition |
| Journal Title: | Cell Reports Medicine |
| Volume: | 5 |
| Issue: | 11 |
| ISSN: | 2666-3791 |
| Publisher: | Cell Press |
| Date Published: | 2024-11-19 |
| Start Page: | 101818 |
| Language: | English |
| DOI: | 10.1016/j.xcrm.2024.101818 |
| PUBMED: | 39488215 |
| PROVIDER: | scopus |
| PMCID: | PMC11604403 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors are MSK authors: Sandra Misale and Neal Rosen -- Source: Scopus |
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