Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis

Our plain-English summary of Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis, by J. Cooper, Q. Xu, L. Zhou, et al (Molecular Cancer Therapeutics, 2017).

The study

• Authors: J. Cooper, Q. Xu, L. Zhou, M. Pavlovic, V. Ojeda, K. Moulick, E. de Stanchina, J.T. Poirier, M. Zauderer, C.M. Rudin, M.A. Karajannis, C.O. Hanemann, F.G. Giancotti
• Journal: Molecular Cancer Therapeutics
• Published: 2017;16(8):1693-1704
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4DCAF1, thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells. In addition, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRL) involved in DNA repair. However, even in combination with chemotherapy, MLN4924 does not exhibit significant preclinical activity. Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4DCAF1 Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts. These results provide preclinical rationale for the use of NAE inhibitors in combination with mTOR/PI3K inhibitors in NF2-mutant tumors. Mol Cancer Ther; 16(8); 1693-704. ©2017 AACR.

©2017 American Association for Cancer Research.

In plain English

This laboratory study examined mesothelioma and schwannoma cells with loss of NF2/Merlin function. It did not study asbestos exposure or treat patients. The authors tested the drug MLN4924 in cell lines, schwannoma cells from NF2 patients, and mice carrying human malignant pleural mesothelioma tumors. The MLN4924 dose that halved growth was 0.55 micromolar or lower in 5 of 7 NF2-mutant mesothelioma lines but about 2 micromolar or higher in untransformed mesothelial cells and 2 of 4 NF2-normal mesothelioma lines. It was 0.28 micromolar in NF2-null mouse schwannoma cells and 2.7 micromolar in a matched immortalized mouse Schwann cell line with normal Nf2. In mice, MLN4924 plus cisplatin and pemetrexed slowed tumor growth significantly more than either alone. It did not completely stop tumor growth or shrink tumors; the authors called this activity limited. MLN4924 did not reduce signaling through a second growth pathway, mTOR. Adding the mTOR/PI3K inhibitor GDC-0980 to MLN4924 completely suppressed tumor growth in mice with cell-line and patient-derived mesothelioma tumors. The authors concluded this gives a preclinical rationale for combining the two kinds of drug in NF2-mutant tumors.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using cell lines, primary human cells, and mouse xenograft experiments (human tumors grown in mice), including a patient-derived xenograft
• Who was studied: The study used several kinds of material: mesothelial and mesothelioma cell lines (NF2-mutant and NF2-wild type); Nf2-null mouse schwannoma cells (FC-1801) and a matched immortalized Nf2-wild type mouse Schwann cell line (FH-912); primary schwannoma cells from NF2 patients and normal Schwann cells; female NSG mice carrying VAMT or Meso-10 tumors; and an NF2-mutant epithelioid malignant pleural mesothelioma patient-derived xenograft (MSK-LX19).
• Exposure: No asbestos exposure was studied. The exposures were drugs: MLN4924 (90 or 120 mg/kg in mice), cisplatin (3 mg/kg weekly) plus pemetrexed (100 mg/kg), and the mTOR/PI3K inhibitor GDC-0980 (5 mg/kg by mouth). The authors also depleted DCAF1 genetically.
• Main results:
  • The MLN4924 dose that cut growth by half (GI50) was 0.28 µM in Nf2-null mouse schwannoma cells (FC-1801). It was 2.7 µM in the matched immortalized Nf2-wild type Schwann cell line (FH-912), which is about ten-fold less sensitive.
  • Depleting DCAF1 reduced proliferation of the NF2-mutant mesothelioma lines Meso-33 and VAMT by 50-70% within 4 days, compared with controls.
  • The MLN4924 GI50 was about 2 μM or higher in untransformed Met5a and LP9 mesothelial cells and in 2 of 4 NF2-wild type mesothelioma lines. It was 0.55 μM or lower in 5 of 7 NF2-mutant mesothelioma lines.
  • Neither DCAF1 depletion nor MLN4924 reduced mTORC1 pathway signaling in NF2-mutant cells.
  • In mice with VAMT or Meso-10 mesothelioma tumors, MLN4924 plus pemetrexed and cisplatin inhibited tumor growth significantly more than either treatment alone.
  • MLN4924, even with chemotherapy, did not completely suppress tumor growth or cause tumor regression.
  • In mice with VAMT tumors, GDC-0980 alone was marginally more effective than MLN4924 alone, but the difference was not statistically significant. The combination of MLN4924 and GDC-0980 completely suppressed tumor growth.
  • MLN4924 suppressed proliferation of primary human NF2-mutant schwannoma cells but did not affect NF2-wild type Schwann cells. The combination with GDC-0980 significantly reduced schwannoma cell proliferation in vitro.
  • In the MSK-LX19 patient-derived mesothelioma xenograft, MLN4924 alone and GDC-0980 alone significantly reduced tumor growth (P less than 0.01 and P less than 0.001). The combination completely suppressed tumor growth (P less than 0.001).
• The authors' conclusion: The authors concluded that the results provide preclinical rationale for using NEDD8-activating enzyme inhibitors together with mTOR/PI3K inhibitors in NF2-mutant tumors.
• Limitations the authors state:
  • Some cell lines were neither tested nor authenticated.
  • The NF2-mutant Meso-9 and Meso-10 lines were not fully sequenced, so their relative insensitivity to MLN4924 might be due to an unidentified genetic alteration.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Merlin, Pleural Mesothelioma, Targeted Therapy, Chemotherapy.

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• Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells — M. Bonelli, R. Terenziani, et al. (2020)
• Loss of NF2 Induces TGFβ Receptor 1-mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome — J.H. Cho, A.Y. Oh, et al. (2018)
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