Purpose: In neurofibromatosis type 1 (NF1) and in highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), constitutively active RAS-GTP and increasedMAPK signaling are important in tumorigenesis. Dual specificity phosphatases (DUSPs) are negative regulators of MAPK signaling that dephosphorylate p38, JNK, and ERK in different settings. Although often acting as tumor suppressors, DUSPs may also act as oncogenes, helping tumor cells adapt to high levels of MAPK signaling. We hypothesized that inhibiting DUSPs might be selectively toxic to cells from NF1-driven tumors. Experimental Design: We examined DUSP gene and protein expression in neurofibroma and MPNSTs. We used small hairpin RNA (shRNA) to knock down DUSP1 and DUSP6 to evaluate cell growth, downstream MAPK signaling, and mechanisms of action. We evaluated the DUSP inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro- 1H-inden-1-one (BCI), in MPNST cell lines and in cell-line and patient-derived MPNST xenografts. Results: DUSP1 and DUSP6 are expressed in NF1-deleted tumors. Knockdown of DUSP1 and DUSP6, alone or in combination, reduced MPNST cell growth and led to ERK and JNK hyperactivation increasing downstream TP53 and p-ATM. The DUSP inhibitor, BCI, diminished the survival of NF1-deleted Schwann cells and MPNST cell lines through activation of JNK. In vivo, treatment of an established cellline xenograft or a novel patient-derived xenograft (PDX) of MPNSTs with BCI increased ERK and JNK activation, caused tumor necrosis and fibrosis, and reduced tumor volume in one model. Conclusions: Targeting DUSP1 and DUSP6 genetically or with BCI effectively inhibits MPNST cell growth and promotes cell death, in vitro and in xenograft models. The data support further investigation of DUSP inhibition in MPNSTs.
Bibliographical noteFunding Information:
The authors thank Dr. Meenu Kesarwani for providing reagents and critical review of the manuscript, Dr. Tilat Rizvi for advice on IHC, Jonathan Fletcher for tumor dissection assistance, and Kierra Ware for immunoblot assistance. This work was supported by R01 NS086219 (to D.A. Largaespada and N. Ratner), a grant from the Children's Tumor Foundation-Synodos (to D.A. Largaespada),
The authors thank Dr. Meenu Kesarwani for providing reagents and critical review of themanuscript, Dr. Tilat Rizvi for advice on IHC, Jonathan Fletcher for tumor dissection assistance, and Kierra Ware for immunoblot assistance. This work was supported by R01 NS086219 (to D.A. Largaespada and N. Ratner), a grant from the Children's Tumor Foundation-Synodos (to D.A. Largaespada), and CancerFree KIDS grants (to A. Ramkissoon). A.A.Miller was supported by a summer fellowship (NIH T35DK060444).
© 2019 American Association for Cancer Research.