399
Views
0
CrossRef citations to date
0
Altmetric
Review

NF1 alterations in cancers: therapeutic implications in precision medicine

, , & ORCID Icon
Pages 941-957 | Received 06 May 2023, Accepted 24 Sep 2023, Published online: 03 Oct 2023

References

  • Upadhyaya M. NF1 gene structure and NF1 genotype/phenotype correlations. Neurofibromatoses. 2008;16:46–62.
  • Bergoug M, Doudeau M, Godin F, et al. Neurofibromin structure, functions and regulation. Cells. 2020;9(11):2365. doi: 10.3390/cells9112365
  • Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648–657. doi: 10.1038/ncb839
  • De Luca A, Maiello MR, D’Alessio A, et al. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 2012;16(Suppl 2):S17–27. doi: 10.1517/14728222.2011.639361
  • Li Y, Bollag G, Clark R, et al. Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell. 1992;69(2):275–281. doi: 10.1016/0092-8674(92)90408-5
  • Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173(2):321–337.e10. doi: 10.1016/j.cell.2018.03.035
  • Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–404. doi: 10.1158/2159-8290.CD-12-0095
  • Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioportal. Sci Signal. 2013;6(269):l1. doi: 10.1126/scisignal.2004088
  • Stenson PD, Mort M, Ball EV, et al. The human gene mutation database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139(10):1197–1207. doi: 10.1007/s00439-020-02199-3
  • NIH (National Institutes of Health Consensus Development Conference). Neurofibromatosis: conference statement. Arch Neurol. 1988; 45:575–578. doi: 10.1001/archneur.1988.00520290115023
  • Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506–1513. doi: 10.1038/s41436-021-01170-5
  • Hernández-Imaz E, Martín Y, Conti de L, et al. Functional analysis of mutations in exon 9 of NF1 reveals the presence of several elements regulating splicing. PLoS One. 2015;10(10):e0141735. doi: 10.1371/journal.pone.0141735
  • Bergqvist C, Servy A, Valeyrie-Allanore L, et al. Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis. 2020;15(1):37. doi: 10.1186/s13023-020-1310-3
  • Dunning-Davies BM, Parker APJ. Annual review of children with neurofibromatosis type 1. Arch Dis Child Educ Pract Ed. 2016;101(2):102–111. doi: 10.1136/archdischild-2014-308084
  • Duong TA, Sbidian E, Valeyrie-Allanore L, et al. Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980-2006 in France. Orphanet J Rare Dis. 2011;6(1):18. doi: 10.1186/1750-1172-6-18
  • Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet. 2001;68(5):1110–1118. doi: 10.1086/320121
  • Ratner N, Miller SJ. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015;15(5):290–301. doi: 10.1038/nrc3911
  • Serra E, Rosenbaum T, Winner U, et al. Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Hum Mol Genet. 2000;9:3055–3064. doi: 10.1093/hmg/9.20.3055
  • Kiuru M, Busam KJ. The NF1 gene in tumor syndromes and melanoma. Lab Investig J Tech Methods Pathol. 2017;97(2):146–157. doi: 10.1038/labinvest.2016.142
  • Rabab’h O, Gharaibeh A, Al-Ramadan A, et al. Pharmacological approaches in neurofibromatosis type 1-associated nervous System tumors. Cancers. 2021;13(15):3880. doi: 10.3390/cancers13153880
  • Marques C, Unterkircher T, Kroon P, et al. NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1. Elife. 2021;10:e64846. doi: 10.7554/eLife.64846
  • Walker JA, Upadhyaya M. Emerging therapeutic targets for neurofibromatosis type 1. Expert Opin Ther Targets. 2018;22(5):419–437. doi: 10.1080/14728222.2018.1465931
  • De Raedt T, Beert E, Pasmant E, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014;514(7521):247–251. doi: 10.1038/nature13561
  • Luscan A, Shackleford G, Masliah-Planchon J, et al. The activation of the WNT signaling pathway is a hallmark in neurofibromatosis type 1 tumorigenesis. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(2):358–371. doi: 10.1158/1078-0432.CCR-13-0780
  • Madanikia SA, Bergner A, Ye X, et al. Increased risk of breast cancer in women with NF1. Am J Med Genet A. 2012;158A:3056–3060. doi: 10.1002/ajmg.a.35550
  • Suarez-Kelly LP, Yu L, Kline D, et al. Increased breast cancer risk in women with neurofibromatosis type 1: a meta-analysis and systematic review of the literature. Hered Cancer Clin Pract. 2019;17(1):12. doi: 10.1186/s13053-019-0110-z
  • Zinnamosca L, Petramala L, Cotesta D, et al. Neurofibromatosis type 1 (NF1) and pheochromocytoma: prevalence, clinical and cardiovascular aspects. Arch Dermatol Res. 2011;303(5):317–325. doi: 10.1007/s00403-010-1090-z
  • Moramarco J, El Ghorayeb N, Dumas N, et al. Pheochromocytomas are diagnosed incidentally and at older age in neurofibromatosis type 1. Clin Endocrinol (Oxf). 2017;86(3):332–339. doi: 10.1111/cen.13265
  • Nishida T, Tsujimoto M, Takahashi T, et al. Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. J Gastroenterol. 2016;51(6):571–578. doi: 10.1007/s00535-015-1132-6
  • Giuly JA, Picand R, Giuly D, et al. Von Recklinghausen disease and gastrointestinal stromal tumors. Am J Surg. 2003;185(1):86–87. doi: 10.1016/S0002-9610(02)01111-X
  • Crucis A, Richer W, Brugières L, et al. Rhabdomyosarcomas in children with neurofibromatosis type I: a national historical cohort. Pediatr Blood Cancer. 2015;62(10):1733–1738. doi: 10.1002/pbc.25556
  • Anderson MK, Johnson M, Thornburg L, et al. A review of Selumetinib in the treatment of neurofibromatosis type 1-related plexiform neurofibromas. Ann Pharmacother. 2022;56:716–726. doi: 10.1177/10600280211046298
  • Foiadelli T, Naso M, Licari A, et al. Advanced pharmacological therapies for neurofibromatosis type 1-related tumors. Acta Bio Medica Atenei Parm. 2020;91:101–114.
  • Báez-Flores J, Rodríguez-Martín M, Lacal J. The therapeutic potential of neurofibromin signaling pathways and binding partners. Commun Biol. 2023;6(1):1–13. doi: 10.1038/s42003-023-04815-0
  • Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430–1442. doi: 10.1056/NEJMoa1912735
  • Fangusaro J, Onar-Thomas A, Poussaint TY, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20(7):1011–1022. doi: 10.1016/S1470-2045(19)30277-3
  • Galvin R, Watson AL, Largaespada DA, et al. Neurofibromatosis in the era of precision medicine: development of MEK inhibitors and recent successes with Selumetinib. Curr Oncol Rep. 2021;23(4):45. doi: 10.1007/s11912-021-01032-y
  • McCowage GB, Mueller S, Pratilas CA, et al. Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)–associated plexiform neurofibroma: a phase I/IIa study. J Clin Oncol. 2018;15(suppl):10504–10504. doi: 10.1200/JCO.2018.36.15_suppl.10504
  • Weiss BD, Wolters PL, Plotkin SR, et al. NF106: a neurofibromatosis clinical trials consortium phase II trial of the MEK inhibitor mirdametinib (PD-0325901) in adolescents and adults with NF1-related plexiform neurofibromas. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(7):797–806. doi: 10.1200/JCO.20.02220
  • Trippett T, Toledano H, Campbell Hewson Q, et al. Cobimetinib in pediatric and young adult patients with Relapsed or Refractory solid tumors (iMATRIX-cobi): a multicenter, phase I/II study. Target Oncol. 2022;17(3):283–293. doi: 10.1007/s11523-022-00888-9
  • de Blank PMK, Gross AM, Akshintala S, et al. MEK inhibitors for neurofibromatosis type 1 manifestations: clinical evidence and consensus. Neuro Oncol. 2022;24:1845–1856. doi: 10.1093/neuonc/noac165
  • Morris EJ, Jha S, Restaino CR, et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 2013;3(7):742–750. doi: 10.1158/2159-8290.CD-13-0070
  • Wang J, Pollard K, Allen AN, et al. Combined inhibition of SHP2 and MEK is effective in models of NF1-deficient malignant peripheral nerve sheath tumors. Cancer Res. 2020;80(23):5367–5379. doi: 10.1158/0008-5472.CAN-20-1365
  • Nichols RJ, Haderk F, Stahlhut C, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018;20(9):1064–1073. doi: 10.1038/s41556-018-0169-1
  • Aplin AE, Capparelli C. Combined SHPments: an effective therapeutic strategy for MPNST. Cancer Res. 2021;81(2):266–267. doi: 10.1158/0008-5472.CAN-20-3834
  • Drilon A, Sharma MR, Johnson ML, et al. SHP2 inhibition sensitizes diverse oncogene-addicted solid tumors to re-treatment with targeted therapy. Cancer Discov. 2023;13(8):1789–1801. doi: 10.1158/2159-8290.CD-23-0361
  • Varin J, Poulain L, Hivelin M, 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):35753–35767. doi: 10.18632/oncotarget.7099
  • Johannessen CM, Johnson BW, Williams SMG, et al. TORC1 is essential for NF1-associated malignancies. Curr Biol. 2008;18(1):56–62. doi: 10.1016/j.cub.2007.11.066
  • Weiss B, Widemann BC, Wolters P, et al. Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis clinical trials consortium phase II study. Neuro Oncol. 2015;17(4):596–603. doi: 10.1093/neuonc/nou235
  • Slopis JM, Arevalo O, Bell CS, et al. Treatment of disfiguring Cutaneous lesions in neurofibromatosis-1 with everolimus: a phase II, open-label, single-arm trial. Drugs RD. 2018;18(4):295–302. doi: 10.1007/s40268-018-0248-6
  • Ullrich NJ, Prabhu SP, Reddy AT, et al. A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1–associated pediatric low-grade glioma: a neurofibromatosis clinical trials consortium study. Neuro Oncol. 2020;22(10):1527–1535. doi: 10.1093/neuonc/noaa071
  • Williams KB, Largaespada DA. New model systems and the development of targeted therapies for the treatment of neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Genes. 2020;11(5):11. doi: 10.3390/genes11050477
  • K A, L Y, Sh O, et al. Targeting Refractory sarcomas and malignant peripheral nerve sheath tumors in a phase I/II study of sirolimus in combination with ganetespib (SARC023). Sarcoma. 2020 [cited 2022 Oct 31];2020:1–8. doi: 10.1155/2020/5784876.
  • Widemann BC, Lu Y, Reinke D, et al. Targeting sporadic and neurofibromatosis type 1 (NF1) related Refractory malignant peripheral nerve sheath tumors (MPNST) in a phase II study of everolimus in combination with Bevacizumab (SARC016). Sarcoma. 2019;2019:e7656747. doi: 10.1155/2019/7656747
  • Nishida Y, Urakawa H, Nakayama R, et al. Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors. Int J Cancer. 2021;148(1):140–149. doi: 10.1002/ijc.33201
  • Schuetze SM, Wathen JK, Lucas DR, et al. SARC009: phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma. Cancer. 2016;122(6):868–874. doi: 10.1002/cncr.29858
  • Fisher MJ, Shih C-S, Rhodes SD, et al. Cabozantinib for neurofibromatosis type 1–related plexiform neurofibromas: a phase 2 trial. Nat Med. 2021;27(1):165–173. doi: 10.1038/s41591-020-01193-6
  • Scheer M, Leisz S, Sorge E, et al. Neurofibromatosis type 1 gene alterations define specific features of a subset of glioblastomas. Int J Mol Sci. 2022;23:352. doi: 10.3390/ijms23010352
  • Bewley AF, Akinwe TM, Turner TN, et al. Neurofibromatosis-1 gene mutational profiles differ between syndromic disease and sporadic cancers. Neurol Genet [Internet]. 2022 [cited 2022 Aug 17];8(4):e200003. doi: 10.1212/NXG.0000000000200003
  • Kan Z, Jaiswal BS, Stinson J, et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature. 2010;466(7308):869–873. doi: 10.1038/nature09208
  • Akbani R, Akdemir KC, Aksoy BA, et al. Genomic classification of Cutaneous melanoma. Cell. 2015;161(7):1681–1696. doi: 10.1016/j.cell.2015.05.044
  • Stieglitz E, Taylor-Weiner AN, Chang TY, et al. The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet. 2015;47(11):1326–1333. doi: 10.1038/ng.3400
  • Philpott C, Tovell H, Frayling IM, et al. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017;11(1):13. doi: 10.1186/s40246-017-0109-3
  • Pasmant E, Parfait B, Luscan A, et al. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet EJHG. 2015;23(5):596–601. doi: 10.1038/ejhg.2014.145
  • Wiesner T, Kiuru M, Scott SN, et al. NF1 mutations are common in desmoplastic melanoma. Am J Surg Pathol. 2015;39(10):1357–1362. doi: 10.1097/PAS.0000000000000451
  • Krauthammer M, Kong Y, Bacchiocchi A, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015;47(9):996–1002. doi: 10.1038/ng.3361
  • Rajkumar S, Berry D, Heney KA, et al. Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor combination therapy. Cell Rep. 2022;39(1):110634. doi: 10.1016/j.celrep.2022.110634
  • Ward AF, Braun BS, Shannon KM. Targeting oncogenic Ras signaling in hematologic malignancies. Blood. 2012;120(17):3397–3406. doi: 10.1182/blood-2012-05-378596
  • Parkin B, Ouillette P, Wang Y, et al. NF1 inactivation in adult acute myelogenous leukemia. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16(16):4135–4147. doi: 10.1158/1078-0432.CCR-09-2639
  • Eisfeld A-K, Kohlschmidt J, Mrózek K, et al. NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome. Leukemia. 2018;32(12):2536–2545. doi: 10.1038/s41375-018-0147-4
  • Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–1812. doi: 10.1126/science.1164382
  • Tlemsani C, Pécuchet N, Gruber A, et al. NF1 mutations identify molecular and clinical subtypes of lung adenocarcinomas. Cancer Med. 2019;8(9):4330–4337. doi: 10.1002/cam4.2175
  • Bowman L, Tiu R, Smyth EN, et al. Clinical characteristics, treatments, and concurrent mutations in non–small cell lung cancer patients with NF1 mutations. Clin Lung Cancer. 2021;22(1):32–41.e1. doi: 10.1016/j.cllc.2020.09.011
  • Redig AJ, Capelletti M, Dahlberg SE, et al. Clinical and molecular characteristics of NF1-mutant lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(13):3148–3156. doi: 10.1158/1078-0432.CCR-15-2377
  • Kitajima S, Barbie DA. RASA1/NF1-mutant lung cancer: racing to the clinic? Clin Cancer Res. 2018;24(6):1243–1245. doi: 10.1158/1078-0432.CCR-17-3597
  • Griffith OL, Spies NC, Anurag M, et al. The prognostic effects of somatic mutations in ER-positive breast cancer. Nat Commun. 2018;9(1):3476. doi: 10.1038/s41467-018-05914-x
  • Pearson A, Proszek P, Pascual J, et al. Inactivating NF1 mutations are enriched in advanced breast cancer and contribute to endocrine therapy resistance. Clin Cancer Res. 2020;26(3):608–622. doi: 10.1158/1078-0432.CCR-18-4044
  • Sangha N, Wu R, Kuick R, et al. Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations. Neoplasia N Y N. 2008;10:1362–1372. following 1372. doi: 10.1593/neo.08784
  • Arai H, Elliott A, Millstein J, et al. Molecular characteristics and clinical outcomes of patients with neurofibromin 1-altered metastatic colorectal cancer. Oncogene. 2022;41(2):260–267. doi: 10.1038/s41388-021-02074-z
  • Whittaker SR, Theurillat J-P, Van Allen E, et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 2013;3(3):350–362. doi: 10.1158/2159-8290.CD-12-0470
  • Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):782–789. doi: 10.1016/S1470-2045(12)70269-3
  • Wisinski KB, Flamand Y, Wilson MA, et al. Trametinib in patients with NF1-, GNAQ-, or GNA11-mutant tumors: results from the NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocols S1 and S2. JCO Precis Oncol. 2023;7(7):e2200421. doi: 10.1200/PO.22.00421
  • Vitanza NA, Khalatbari H, Ermoian R, et al. Molecularly targeted treatments for NF1-mutant diffuse intrinsic pontine glioma. J Appl Lab Med. 2021;6(2):550–553. doi: 10.1093/jalm/jfaa086
  • Hayashi T, Desmeules P, Smith RS, et al. RASA1 and NF1 are preferentially co-mutated and define a distinct genetic subset of smoking-associated non–small cell lung carcinomas sensitive to MEK inhibition. Clin Cancer Res. 2018;24(6):1436–1447. doi: 10.1158/1078-0432.CCR-17-2343
  • Kurimchak AM, Shelton C, Herrera-Montávez C, et al. Intrinsic resistance to MEK inhibition through BET protein-mediated kinome reprogramming in NF1-deficient ovarian cancer. Mol Cancer Res MCR. 2019;17:1721–1734. doi: 10.1158/1541-7786.MCR-18-1332
  • Cai J, Jacob S, Kurupi R, et al. High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition. Cell Rep. 2022;40(4):111095. doi: 10.1016/j.celrep.2022.111095
  • Hong A, Piva M, Liu S, et al. Durable suppression of acquired MEK inhibitor resistance in cancer by sequestering MEK from ERK and promoting antitumor T-cell immunity. Cancer Discov. 2021;11(3):714–735. doi: 10.1158/2159-8290.CD-20-0873
  • Maertens O, Kuzmickas R, Manchester HE, et al. MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability in BRAF-, NRAS-, and NF1-mutant melanomas. Cancer Discov. 2019;9(4):526–545. doi: 10.1158/2159-8290.CD-18-0879
  • Jour G, Illa-Bochaca I, Ibrahim M, et al. Genomic and transcriptomic analyses of NF1-mutant melanoma identify potential targeted approach for treatment. J Invest Dermatol. 2023;143(3):444–455.e8. doi: 10.1016/j.jid.2022.07.022
  • Alon M, Arafeh R, Lee JS, et al. CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma. Oncotarget. 2018;9(58):31264–31277. doi: 10.18632/oncotarget.25805
  • Devarakonda S, Pellini B, Verghese L, et al. A phase II study of everolimus in patients with advanced solid malignancies with TSC1, TSC2, NF1, NF2 or STK11 mutations. J Thorac Dis. 2021;13(7):4054–4062. doi: 10.21037/jtd-21-195
  • Owonikoko TK, Harvey RD, Carthon B, et al. A phase I study of safety, pharmacokinetics, and pharmacodynamics of concurrent everolimus and buparlisib treatment in advanced solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2020;26(11):2497–2505. doi: 10.1158/1078-0432.CCR-19-2697
  • Hassan A, Pestana RC, Parkes A. Systemic options for malignant peripheral nerve sheath tumors. Curr Treat Options Oncol. 2021;22(4):33. doi: 10.1007/s11864-021-00830-7
  • Manji GA, Van Tine BA, Lee SM, et al. A phase 1 study of the combination of pexidartinib and sirolimus to target tumor associated macrophages in unresectable sarcoma and malignant peripheral nerve sheath tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2021;27:5519–5527. doi: 10.1158/1078-0432.CCR-21-1779
  • Abecunas C, Whitehead CE, Ziemke EK, et al. Loss of NF1 in melanoma confers sensitivity to SYK kinase inhibition. Cancer Res. 2023;83(2):316–331. doi: 10.1158/0008-5472.CAN-22-0883
  • Espinosa E, Márquez-Rodas I, Soria A, et al. Predictive factors of response to immunotherapy-a review from the Spanish melanoma group (GEM). Ann Transl Med. 2017;5:389. doi: 10.21037/atm.2017.08.10
  • Bai R, Lv Z, Xu D, et al. Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomark Res. 2020;8(1):34. doi: 10.1186/s40364-020-00209-0
  • Johnson DB, Frampton GM, Rioth MJ, et al. Targeted next generation sequencing identifies markers of response to PD-1 blockade. Cancer Immunol Res. 2016;4(11):959–967. doi: 10.1158/2326-6066.CIR-16-0143
  • Madore J, Strbenac D, Vilain R, et al. PD-L1 negative status is associated with lower mutation Burden, differential expression of immune-related genes, and worse survival in stage III melanoma. Clin Cancer Res. 2016;22(15):3915–3923. doi: 10.1158/1078-0432.CCR-15-1714
  • Eroglu Z, Zaretsky JM, Hu-Lieskovan S, et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature. 2018;553(7688):347–350. doi: 10.1038/nature25187
  • Thielmann CM, Chorti E, Matull J, et al. NF1-mutated melanomas reveal distinct clinical characteristics depending on tumour origin and respond favourably to immune checkpoint inhibitors. Eur J Cancer Oxf Engl 1990. 2021;159:113–124. doi: 10.1016/j.ejca.2021.09.035
  • Li X, Sun J, Wang L. NF1-mutant cancer and immune checkpoint inhibitors: a large database analysis. Clin Lung Cancer. 2021;22(5):480–481. doi: 10.1016/j.cllc.2021.03.002
  • Kauffmann-Guerrero D, Tufman A, Kahnert K, et al. Response to checkpoint inhibition in non-small cell lung cancer with molecular driver alterations. Oncol Res Treat. 2020;43(6):289–298. doi: 10.1159/000506842
  • Nakasuka T, Ohashi K, Watanabe H, et al. A case of dramatic reduction in cancer-associated thrombus following initiation of pembrolizumab in patient with a poor performance status and PD-L1+ lung adenocarcinoma harboring CCDC6–RET fusion gene and NF1/TP53 mutations. Lung Cancer. 2021;156:1–4. doi: 10.1016/j.lungcan.2021.03.022
  • Tao J, Sun D, Dong L, et al. Advancement in research and therapy of NF1 mutant malignant tumors. Cancer Cell Int. 2020;20(1):492. doi: 10.1186/s12935-020-01570-8
  • Su J, Ruan S, Dai S, et al. NF1 regulates apoptosis in ovarian cancer cells by targeting MCL1 via miR-142–5p. Pharmacogenomics. 2019;20(3):155–165. doi: 10.2217/pgs-2018-0161
  • Shi Z-D, Hao L, Han X-X, et al. Targeting HNRNPU to overcome cisplatin resistance in bladder cancer. Mol Cancer. 2022;21(1):37. doi: 10.1186/s12943-022-01517-9
  • Harder A. MEK inhibitors - novel targeted therapies of neurofibromatosis associated benign and malignant lesions. Biomark Res. 2021;9(1):26. doi: 10.1186/s40364-021-00281-0
  • Khaddour K, Maahs L, Avila-Rodriguez AM, et al. Melanoma targeted therapies beyond BRAF-Mutant melanoma: potential druggable mutations and novel treatment approaches. Cancers. 2021;13(22):5847. doi: 10.3390/cancers13225847
  • Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLOS Med. 2005;2(1):e17. doi: 10.1371/journal.pmed.0020017
  • Arima Y, Hayashi H, Kamata K, et al. Decreased expression of neurofibromin contributes to epithelial-mesenchymal transition in neurofibromatosis type 1. Exp Dermatol. 2010;19:e136–141. doi: 10.1111/j.1600-0625.2009.01017.x
  • Kawachi Y, Maruyama H, Ishitsuka 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):262–265. doi: 10.1111/exd.12115
  • Nussinov R, Tsai C-J, Jang H. Anticancer drug resistance: an update and perspective. Drug Resist Updat Rev Comment Antimicrob Anticancer Chemother. 2021;59:100796. doi: 10.1016/j.drup.2021.100796
  • Maertens O, Johnson B, Hollstein P, et al. Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov. 2013;3(3):338–349. doi: 10.1158/2159-8290.CD-12-0313
  • Deng L-L, Gao G, Deng H-B, et al. Co-occurring genetic alterations predict distant metastasis and poor efficacy of first-line EGFR-TKIs in EGFR-mutant NSCLC. J Cancer Res Clin Oncol. 2019;145(10):2613–2624. doi: 10.1007/s00432-019-03001-2
  • de Bruin EC, Cowell C, Warne PH, et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 2014;4:606–619. doi: 10.1158/2159-8290.CD-13-0741
  • Wang J, Pollard K, Calizo A, et al. Activation of receptor tyrosine kinases mediates acquired resistance to MEK inhibition in malignant peripheral nerve sheath tumors. Cancer Res. 2021;81(3):747–762. doi: 10.1158/0008-5472.CAN-20-1992
  • Kim B-J, Zheng Z-Y, Lei JT, et al. Proteogenomic approaches for the identification of NF1/Neurofibromin-depleted estrogen receptor-positive breast cancers for targeted treatment. Cancer Res Commun. 2023;3:1366–1377. doi: 10.1158/2767-9764.CRC-23-0044
  • Razavi P, Chang MT, Xu G, et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell. 2018;34(3):427–438.e6. doi: 10.1016/j.ccell.2018.08.008
  • Sokol ES, Feng YX, Jin DX, et al. Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2019;30(1):115–123. doi: 10.1093/annonc/mdy497
  • Hölzel M, Huang S, Koster J, et al. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell. 2010;142(2):218–229. doi: 10.1016/j.cell.2010.06.004
  • Sanchez LD, Bui A, Klesse LJ. Targeted therapies for the neurofibromatoses. Cancers. 2021;13(23):6032. doi: 10.3390/cancers13236032
  • Subbiah V. The next generation of evidence-based medicine. Nat Med. 2023;29(1):49–58. doi: 10.1038/s41591-022-02160-z
  • Solares I, Viñal D, Morales-Conejo M, et al. Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. ESMO Open. 2021 [cited 2021 Aug 30];6(4):100223. doi: 10.1016/j.esmoop.2021.100223
  • Klesse LJ, Jordan JT, Radtke HB, et al. The use of MEK inhibitors in neurofibromatosis type 1-associated tumors and management of toxicities. Oncology. 2020;25:e1109–e1116. doi: 10.1634/theoncologist.2020-0069
  • Huang A, Garraway LA, Ashworth A, et al. Synthetic lethality as an engine for cancer drug target discovery. Nat Rev Drug Discov. 2020;19(1):23–38. doi: 10.1038/s41573-019-0046-z
  • Parameswaran S, Kundapur D, Vizeacoumar FS, et al. A road map to personalizing targeted cancer therapies using synthetic lethality. Trends Cancer. 2019;5(1):11–29. doi: 10.1016/j.trecan.2018.11.001

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.