MEK inhibitors lead to PDGFR pathway upregulation and sensitize tumors to RAF dimer inhibitors in NF1-deficient malignant peripheral nerve sheath tumor Journal Article
| Authors: | Miranda-Román, M. A.; Lee, C. J.; Fishinevich, E.; Ran, L.; Patel, A. J.; Yan, J.; Khudoynazarova, M. N.; Warda, S.; Pachai, M. R.; Chen, Y.; Chi, P. |
| Article Title: | MEK inhibitors lead to PDGFR pathway upregulation and sensitize tumors to RAF dimer inhibitors in NF1-deficient malignant peripheral nerve sheath tumor |
| Abstract: | PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive subtype of soft-tissue sarcoma with a high propensity to metastasize and extremely limited treatment options. Loss of the RAS-GAP NF1 leads to sustained RAF/MEK/ERK signaling in MPNST. However, single-agent MEK inhibitors (MEKi) have failed to elicit a sustained inhibition of the MAPK signaling pathway in MPNST. EXPERIMENTAL DESIGN: We used pharmacological, biochemical, and genetic perturbations of the receptor tyrosine kinase and MAPK signaling pathway regulators to investigate the mechanisms of MEKi resistance and evaluated combination therapeutic strategies in various preclinical MPNST models in vitro and in vivo. RESULTS: Here, we report that MEKi treatment resistance in MPNST involves two adaptive pathways: direct transcriptional upregulation of the receptor tyrosine kinase PDGFRβ and MEKi-induced increase in RAF dimer formation and activation of downstream signaling. Although the pharmacologic combination of a MEKi with a PDGFRβ-specific inhibitor was more effective than treatment with the MEKi alone, the combination of the MEKi and RAF dimer inhibitors led to a robust inhibition of MAPK pathway signaling. This combination treatment was effective in vitro and in vivo, as demonstrated by the significant increase in drug synergism and its high effectiveness in decreasing MPNST viability. CONCLUSIONS: Our findings suggest that the combination of MEKis and PDGFR and/or RAF dimer inhibitors can overcome MEKi resistance and may serve as a novel targeted therapeutic strategy for patients with NF1-deficient MPNST, which in turn could impact future clinical investigations for this patient population. ©2024 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | signal transduction; genetics; raf protein; mouse; animal; metabolism; animals; mice; map kinase signaling system; protein kinase inhibitor; drug effect; drug resistance; drug screening; pathology; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; protein kinase inhibitors; gene expression regulation; gene expression regulation, neoplastic; protein multimerization; tumor cell line; neurofibromin; neurofibromin 1; upregulation; up-regulation; drug therapy; nerve sheath tumor; nerve sheath neoplasms; raf kinases; platelet derived growth factor beta receptor; receptor, platelet-derived growth factor beta; mapk signaling; humans; human; pdgfrb protein, human; nf1 protein, human |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 22 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-11-15 |
| Start Page: | 5154 |
| End Page: | 5165 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-1750 |
| PUBMED: | 39269317 |
| PROVIDER: | scopus |
| PMCID: | PMC11565172 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Ping Chi -- Source: Scopus |
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