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Cancer Cell International
Published in: Cancer Cell International 1/2020

Open Access 01-12-2020 | Tyrosine Kinase Inhibitors | Review

Advancement in research and therapy of NF1 mutant malignant tumors

Authors: Junyan Tao, Dantong Sun, Lina Dong, Hua Zhu, Helei Hou

Published in: Cancer Cell International | Issue 1/2020

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Abstract

The NF1 gene encodes neurofibromin, which is one of the primary negative regulatory factors of the Ras protein. Neurofibromin stimulates the GTPase activity of Ras to convert it from an active GTP-bound form to its inactive GDP-bound form through its GTPase activating protein-related domain (GRD). Therefore, neurofibromin serves as a shutdown signal for all vertebrate RAS GTPases. NF1 mutations cause a resultant decrease in neurofibromin expression, which has been detected in many human malignancies, including NSCLC, breast cancer and so on. NF1 mutations are associated with the underlying mechanisms of treatment resistance discovered in multiple malignancies. This paper reviews the possible mechanisms of NF1 mutation-induced therapeutic resistance to chemotherapy, endocrine therapy and targeted therapy in malignancies. Then, we further discuss advancements in targeted therapy for NF1-mutated malignant tumors. In addition, therapies targeting the downstream molecules of NF1 might be potential novel strategies for the treatment of advanced malignancies.
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Literature
1.
Ferlay J, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941–53.PubMedCrossRef
2.
Ma WW, Adjei AA. Novel agents on the horizon for cancer therapy. CA Cancer J Clin. 2009;59(2):111–37.PubMedCrossRef
3.
Ramalingam SS, Owonikoko TK, Khuri FR. Lung cancer: New biological insights and recent therapeutic advances. CA Cancer J Clin. 2011;61(2):91–112.PubMedCrossRef
4.
Vogel CL, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3):719–26.PubMedCrossRef
5.
6.
Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol. 2007;6(4):340–51.PubMedCrossRef
7.
Maertens O, et al. Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov. 2013;3(3):338–49.PubMedCrossRef
8.
9.
Cawthon RM, et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990;62(1):193–201.PubMedCrossRef
10.
11.
Viskochil D, et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990;62(1):187–92.PubMedCrossRef
12.
Wallace MR, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990;249(4965):181–6.PubMedCrossRef
13.
Stenson PD, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136(6):665–77.PubMedPubMedCentralCrossRef
14.
Daston MM, et al. The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron. 1992;8(3):415–28.PubMedCrossRef
15.
16.
17.
Hollstein PE, Cichowski K. Identifying the Ubiquitin Ligase complex that regulates the NF1 tumor suppressor and Ras. Cancer Discov. 2013;3(8):880–93.PubMedCrossRef
18.
Gutmann DH, et al. Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Genome Res. 2013;23(3):431–9.PubMedPubMedCentralCrossRef
19.
20.
21.
Ohba Y, et al. Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J Biol Chem. 2000;275(26):20020–6.PubMedCrossRef
22.
Stites EC, et al. Cooperation between Noncanonical Ras Network Mutations. Cell Rep. 2015;10(5):840.PubMedCrossRef
23.
Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001;294(5545):1299–304.PubMedCrossRef
24.
25.
26.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729–34.PubMedCrossRef
27.
28.
Tsai PI, et al. Neurofibromin mediates FAK signaling in confining synapse growth at Drosophila neuromuscular junctions. J Neurosci. 2012;32(47):16971–81.PubMedPubMedCentralCrossRef
29.
30.
Chao RC, et al. Therapy-induced malignant neoplasms in Nf1 mutant mice. Cancer Cell. 2005;8(4):337–48.PubMedCrossRef
31.
Choi G, et al. Genetically mediated Nf1 loss in mice promotes diverse radiation-induced tumors modeling second malignant neoplasms. Cancer Res. 2012;72(24):6425–34.PubMedPubMedCentralCrossRef
32.
Nakamura JL, et al. Dose-dependent effects of focal fractionated irradiation on secondary malignant neoplasms in Nf1 mutant mice. Cancer Res. 2011;71(1):106–15.PubMedPubMedCentralCrossRef
33.
Wertz IE, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471(7336):110–4.PubMedCrossRef
34.
35.
Su J, et al. NF1 regulates apoptosis in ovarian cancer cells by targeting MCL1 via miR-142-5p. Pharmacogenomics. 2019;20(3):155–65.PubMedCrossRef
36.
Sokol ES, et al. Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer. Ann Oncol. 2019;30(1):115–23.PubMedCrossRef
37.
Beauchamp EM, et al. Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss. Mol Cancer Ther. 2014;13(2):475–82.PubMedCrossRef
38.
Johannessen CM, et al. TORC1 is essential for NF1-associated malignancies. Curr Biol. 2008;18(1):56–62.PubMedCrossRef
39.
Jousma E, et al. Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1. Pediatr Blood Cancer. 2015;62(10):1709–16.PubMedPubMedCentralCrossRef
40.
Varin J, et al. Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells. Oncotarget. 2016;7(24):35753–67.PubMedPubMedCentralCrossRef
41.
42.
Qiao G, et al. Neurofibromin 1 expression is negatively correlated with malignancy and prognosis of epithelial ovarian cancer. Int J Clin Exp Pathol. 2019;12(5):1702–12.PubMedPubMedCentral
43.
Balch WE, et al. Adapting proteostasis for disease intervention. Science. 2008;319(5865):916–9.CrossRef
44.
Mendillo ML, et al. HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell. 2012;150(3):549–62.PubMedPubMedCentralCrossRef
45.
46.
47.
48.
49.
Shapira S, et al. The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways. Cell Death Differ. 2007;14(5):895–906.PubMedCrossRef
50.
Thiery JP, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.PubMedCrossRef
51.
Frederick BA, et al. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther. 2007;6(6):1683–91.PubMedCrossRef
52.
Rho JK, et al. Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer. 2009;63(2):219–26.PubMedCrossRef
53.
Thomson S, et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 2005;65(20):9455–62.PubMedCrossRef
54.
Arima Y, et al. Decreased expression of neurofibromin contributes to epithelial-mesenchymal transition in neurofibromatosis type 1. Exp Dermatol. 2010;19(8):e136–41.PubMedCrossRef
55.
Folkman J. The role of angiogenesis in tumor growth. Semin Cancer Biol. 1992;3(2):65–71.PubMed
56.
Wu M, Wallace MR, Muir D. Nf1 haploinsufficiency augments angiogenesis. Oncogene. 2006;25(16):2297–303.PubMedCrossRef
57.
Thomas SL, De Vries GH. Angiogenic expression profile of normal and neurofibromin-deficient human Schwann cells. Neurochem Res. 2007;32(7):1129–41.PubMedCrossRef
58.
Kawachi Y, et al. NF1 gene silencing induces upregulation of vascular endothelial growth factor expression in both Schwann and non-Schwann cells. Exp Dermatol. 2013;22(4):262–5.PubMedCrossRef
59.
Theeler BJ, et al. Prolonged survival in adult neurofibromatosis type I patients with recurrent high-grade gliomas treated with bevacizumab. J Neurol. 2014;261(8):1559–64.PubMedCrossRef
60.
Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. BioEssays. 1991;13(1):31–6.PubMedCrossRef
61.
Barkan B, et al. The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1. Clin Cancer Res. 2006;12(18):5533–42.PubMedCrossRef
62.
Endo M, et al. Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clin Cancer Res. 2013;19(2):450–61.PubMedCrossRef
63.
Hirokawa Y, et al. Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Cancer Lett. 2007;245(1–2):242–51.PubMedCrossRef
64.
Hirokawa Y, et al. Sichuan pepper extracts block the PAK1/cyclin D1 pathway and the growth of NF1-deficient cancer xenograft in mice. Cancer Biol Ther. 2006;5(3):305–9.PubMedCrossRef
65.
Banerjee S, et al. The neurofibromatosis type 1 tumor suppressor controls cell growth by regulating signal transducer and activator of transcription-3 activity in vitro and in vivo. Cancer Res. 2010;70(4):1356–66.PubMedPubMedCentralCrossRef
66.
Metadata
Title
Advancement in research and therapy of NF1 mutant malignant tumors
Authors
Junyan Tao
Dantong Sun
Lina Dong
Hua Zhu
Helei Hou
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01570-8

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