Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors

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 <i>NF1</i> 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 <i>NF1</i> 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 <i>NF1</i> 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 <i>NF1</i> MPNSTs.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-12-30
DOI
https://doi.org/10.1073/pnas.2407745121
Citations
4
Primary Topic
Neurofibromatosis and Schwannoma Cases
Type
article
Field-Weighted Citation Impact
1.48

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article

Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors

Luis F. Parada, Rebecca Brown, Chi Zhang, Tejus Bale et al.
4 citations
Proceedings of the National Academy of Sciences
Neurofibromatosis and Schwannoma Cases
1.48
article

Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors

Luis F. Parada, Rebecca Brown, Chi Zhang, Tejus Bale, Kwan Ho Tang, Xuanhua Xie, Charlène Iltis, Sameer Farouk Sait, Nicholas D. Socci, Michelle Lien, D. Wade Clapp, Benjamin G. Neel, Steven P. Angus, Shelley A.H. Dixon, Christopher Davis, Daochun Sun
article en
4 citations

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 <i>NF1</i> 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 <i>NF1</i> 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 <i>NF1</i> 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 <i>NF1</i> MPNSTs.

Proceedings of the National Academy of SciencesVol. 122(1)
Indiana University Health (US), Memorial Sloan Kettering Cancer Center (US), Medical College of Wisconsin (US), Sinai Hospital (US), The Mount (GB), Riley Hospital for Children (US), Kettering University (US), Center for Translational Molecular Medicine (NL), College Station Medical Center (US), New York University (US), Indiana University (US)
National Institutes of Health, Congressionally Directed Medical Research Programs
Good health and well-being
Openalex Percentile: Top 16%
Neurofibromatosis and Schwannoma Cases
1.48
DOIOpen Access PDFOpenAlex
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