Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors Journal Article
| Authors: | Sait, S. F.; Tang, K. H.; Angus, S. P.; Brown, R.; Sun, D.; Xie, X.; Iltis, C.; Lien, M.; Socci, N. D.; Bale, T. A.; Davis, C.; Dixon, S. A. H.; Zhang, C.; Wade Clapp, D.; Neel, B. G.; Parada, L. F. |
| Article Title: | Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors |
| Abstract: | Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST models indicates that MEK inhibition has poor antitumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors were performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine (HQ) resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with HQ as a unique treatment approach for NF1 MPNSTs. Copyright © 2024 the Author(s). |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; genetics; drug potentiation; monotherapy; nonhuman; mass spectrometry; mouse; animal; metabolism; animals; mice; animal tissue; neurofibromatosis 1; tumor volume; animal experiment; animal model; antineoplastic activity; immunofluorescence; drug effect; drug resistance; drug screening; pathology; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; drug synergism; tumor cell line; immunoblotting; neurofibromin; neurofibromin 1; hydroxychloroquine; protein tyrosine phosphatase; heterozygosity loss; tumor growth; drug therapy; autophagy; centrifugation; malignant peripheral nerve sheath tumor; mpnst; nerve sheath tumor; nerve sheath neoplasms; protein tyrosine phosphatase shp 2; tumor resistance; polyacrylamide gel electrophoresis; tumor engraftment; nf1; genotyping; complication; affinity chromatography; neurofibromatosis type 1; mitogen activated protein kinase kinase inhibitor; trametinib; protein tyrosine phosphatase, non-receptor type 11; ptpn11 protein, human; humans; human; female; article; rna sequencing; cell counting; cell viability assay; differential expression analysis; gene set enrichment analysis; autophagy (cellular); paired end sequencing; pathway enrichment analysis; bradford assay; nf1 protein, human; shp2 inhibition; protein hydrolysate; cell titer glo assay; multiplexed inhibitor bead mass spectrometry |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 122 |
| Issue: | 1 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2025-01-01 |
| Start Page: | e2407745121 |
| Language: | English |
| DOI: | 10.1073/pnas.2407745121 |
| PUBMED: | 39793045 |
| PROVIDER: | scopus |
| PMCID: | PMC11725864 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Luis F. Parada -- Source: Scopus |
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