Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 6/2023

14-02-2022 | Pulmonary Valve Stenosis | Review Article

An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies

Authors: Jae-Sung Yi, Sravan Perla, Anton M. Bennett

Published in: Cardiovascular Drugs and Therapy | Issue 6/2023

Login to get access

Abstract

The RAS/mitogen-activated protein kinase (MAPK) pathway controls a plethora of developmental and post-developmental processes. It is now clear that mutations in the RAS-MAPK pathway cause developmental diseases collectively referred to as the RASopathies. The RASopathies include Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Costello syndrome. RASopathy patients exhibit a wide spectrum of congenital heart defects (CHD), such as valvular abnormalities and hypertrophic cardiomyopathy (HCM). Since the cardiovascular defects are the most serious and recurrent cause of mortality in RASopathy patients, it is critical to understand the pathological signaling mechanisms that drive the disease. Therapies for the treatment of HCM and other RASopathy-associated comorbidities have yet to be fully realized. Recent developments have shown promise for the use of repurposed antineoplastic drugs that target the RAS-MAPK pathway for the treatment of RASopathy-associated HCM. However, given the impact of the RAS-MAPK pathway in post-developmental physiology, establishing safety and evaluating risk when treating children will be paramount. As such insight provided by preclinical and clinical information will be critical. This review will highlight the cardiovascular manifestations caused by the RASopathies and will discuss the emerging therapies for treatment.
Literature
1.
2.
Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2007;1773(8):1213–26.PubMedCrossRef
3.
4.
Plotnikov A, Zehorai E, Procaccia S, Seger R. The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta. 2011;1813(9):1619–33.PubMedCrossRef
5.
Dard L, Bellance N, Lacombe D, Rossignol R. RAS signalling in energy metabolism and rare human diseases. Biochim Biophys Acta Bioenerg. 2018;1859(9):845–67.PubMedCrossRef
6.
Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005;6(11):827–37.PubMedCrossRef
7.
8.
Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006;7(8):589–600.PubMedCrossRef
9.
Muslin AJ. MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci (Lond). 2008;115(7):203–18.PubMedCrossRef
10.
Sala V, Gallo S, Leo C, Gatti S, Gelb BD, Crepaldi T. Signaling to cardiac hypertrophy: insights from human and mouse RASopathies. Mol Med. 2012;18:938–47.PubMedPubMedCentralCrossRef
11.
Wang Y. Mitogen-activated protein kinases in heart development and diseases. Circulation. 2007;116(12):1413–23.PubMedCrossRef
12.
Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol. 2015;89(9):1401–38.PubMedCrossRef
13.
Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ. Hypertrophic cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease. Heart. 2000;84(5):476–82.PubMedPubMedCentralCrossRef
14.
Dorn GW 2nd. The fuzzy logic of physiological cardiac hypertrophy. Hypertension. 2007;49(5):962–70.PubMedCrossRef
15.
McMullen JR, Jennings GL. Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol. 2007;34(4):255–62.PubMedCrossRef
16.
Brancaccio M, Hirsch E, Notte A, Selvetella G, Lembo G, Tarone G. Integrin signalling: the tug-of-war in heart hypertrophy. Cardiovasc Res. 2006;70(3):422–33.PubMedCrossRef
17.
Delcourt N, Bockaert J, Marin P. GPCR-jacking: from a new route in RTK signalling to a new concept in GPCR activation. Trends Pharmacol Sci. 2007;28(12):602–7.PubMedCrossRef
18.
Olson EN, Schneider MD. Sizing up the heart: development redux in disease. Genes Dev. 2003;17(16):1937–56.PubMedCrossRef
19.
Glennon PE, Kaddoura S, Sale EM, Sale GJ, Fuller SJ, Sugden PH. Depletion of mitogen-activated protein kinase using an antisense oligodeoxynucleotide approach downregulates the phenylephrine-induced hypertrophic response in rat cardiac myocytes. Circ Res. 1996;78(6):954–61.PubMedCrossRef
20.
Yue TL, Gu JL, Wang C, Reith AD, Lee JC, Mirabile RC, et al. Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J Biol Chem. 2000;275(48):37895–901.PubMedCrossRef
21.
Harris IS, Zhang S, Treskov I, Kovacs A, Weinheimer C, Muslin AJ. Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation. 2004;110(6):718–23.PubMedCrossRef
22.
Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest. 2004;114(7):937–43.PubMedPubMedCentralCrossRef
23.
Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, et al. Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci U S A. 2007;104(35):14074–9.PubMedPubMedCentralCrossRef
24.
Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802(4):396–405.PubMedCrossRef
25.
26.
Araki T, Chan G, Newbigging S, Morikawa L, Bronson RT, Neel BG. Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation. Proc Natl Acad Sci U S A. 2009;106(12):4736–41.PubMedPubMedCentralCrossRef
27.
28.
29.
30.
31.
Tajan M, Paccoud R, Branka S, Edouard T, Yart A. The RASopathy family: consequences of germline activation of the RAS/MAPK pathway. Endocr Rev. 2018;39(5):676–700.PubMedCrossRef
32.
Jaffre F, Miller CL, Schanzer A, Evans T, Roberts AE, Hahn A, et al. Inducible pluripotent stem cell-derived cardiomyocytes reveal aberrant extracellular regulated kinase 5 and mitogen-activated protein kinase kinase 1/2 signaling concomitantly promote hypertrophic cardiomyopathy in RAF1-associated Noonan syndrome. Circulation. 2019;140(3):207–24.PubMedPubMedCentralCrossRef
33.
Hernández-Porras I, Guerra C. Modeling RASopathies with genetically modified mouse models. New York: Springer; 2017. p. 379–408.
34.
Weismann CG, Gelb BD. The genetics of congenital heart disease: a review of recent developments. Curr Opin Cardiol. 2007;22(3):200–6.PubMedCrossRef
35.
36.
Fahed AC, Gelb BD, Seidman JG, Seidman CE. Genetics of congenital heart disease: the glass half empty. Circ Res. 2013;112(4):707–20.PubMedCrossRef
37.
Goldmuntz E. The epidemiology and genetics of congenital heart disease. Clin Perinatol. 2001;28(1):1.PubMedCrossRef
38.
Cerrato F, Pacileo G, Limongelli G, Gagliardi MG, Santoro G, Digilio MC, et al. A standard echocardiographic and tissue Doppler study of morphological and functional findings in children with hypertrophic cardiomyopathy compared to those with left ventricular hypertrophy in the setting of Noonan and LEOPARD syndromes. Cardiol Young. 2008;18(6):575–80.PubMedCrossRef
39.
Prendiville TW, Gauvreau K, Tworog-Dube E, Patkin L, Kucherlapati RS, Roberts AE, et al. Cardiovascular disease in Noonan syndrome. Arch Dis Child. 2014;99(7):629–34.PubMedCrossRef
40.
Spartalis M, Tzatzaki E, Athanasiou A, Spartalis E. eComment. Noonan syndrome and biventricular hypertrophic obstructive cardiomyopathy. Interact Cardiovasc Thorac Surg. 2017;25(3):498.PubMedCrossRef
41.
42.
Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contemporary definitions and classification of the cardiomyopathies. Circulation. 2006;113(14):1807–16.PubMedCrossRef
43.
44.
Stoll C, Dott B, Alembik Y, Roth MP. Associated noncardiac congenital anomalies among cases with congenital heart defects. Eur J Med Genet. 2015;58(2):75–85.PubMedCrossRef
45.
Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29(4):465–8.PubMedCrossRef
46.
Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39(1):75–9.PubMedCrossRef
47.
Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331–6.PubMedCrossRef
48.
Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010;42(1):27–9.PubMedCrossRef
49.
Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39(8):1007–12.PubMedCrossRef
50.
Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39(8):1013–7.PubMedCrossRef
51.
Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009;30(4):695–702.PubMedPubMedCentralCrossRef
52.
Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93(1):173–80.PubMedPubMedCentralCrossRef
53.
Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015;52(6):413–21.PubMedCrossRef
54.
Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, et al. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. 2018;20(10):1175–85.PubMedPubMedCentralCrossRef
55.
56.
Stein-Gerlach M, Wallasch C, Ullrich A. SHP-2, SH2-containing protein tyrosine phosphatase-2. Int J Biochem Cell Biol. 1998;30(5):559–66.PubMedCrossRef
57.
Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998;92(4):441–50.PubMedCrossRef
58.
Maroun CR, Naujokas MA, Holgado-Madruga M, Wong AJ, Park M. The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol Cell Biol. 2000;20(22):8513–25.PubMedPubMedCentralCrossRef
59.
Cunnick JM, Meng S, Ren Y, Desponts C, Wang HG, Djeu JY, et al. Regulation of the mitogen-activated protein kinase signaling pathway by SHP2. J Biol Chem. 2002;277(11):9498–504.PubMedCrossRef
60.
Tajan M, de Rocca SA, Valet P, Edouard T, Yart A. SHP2 sails from physiology to pathology. Eur J Med Genet. 2015;58(10):509–25.PubMedCrossRef
61.
Yang W, Klaman LD, Chen B, Araki T, Harada H, Thomas SM, et al. An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev Cell. 2006;10(3):317–27.PubMedCrossRef
62.
Pierpont ME, Digilio MC. Cardiovascular disease in Noonan syndrome. Curr Opin Pediatr. 2018;30(5):601–8.PubMedCrossRef
63.
Sewduth RN, Pandolfi S, Steklov M, Sheryazdanova A, Zhao P, Criem N, et al. The Noonan syndrome gene Lztr1 controls cardiovascular function by regulating vesicular trafficking. Circ Res. 2020;126(10):1379–93.PubMedPubMedCentralCrossRef
64.
Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B. Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr. 1999;135(6):703–6.PubMedCrossRef
65.
Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70(6):1555–63.PubMedPubMedCentralCrossRef
66.
Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003;40(9):704–8.PubMedPubMedCentralCrossRef
67.
Calcagni G, Limongelli G, D’Ambrosio A, Gesualdo F, Digilio MC, Baban A, et al. Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results Int J Cardiol. 2017;245:92–8.PubMed
68.
69.
70.
71.
Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Mingarelli R, et al. LEOPARD syndrome: clinical diagnosis in the first year of life. Am J Med Genet A. 2006;140(7):740–6.PubMedCrossRef
72.
Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002;71(2):389–94.PubMedPubMedCentralCrossRef
73.
Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002;39(8):571–4.PubMedPubMedCentralCrossRef
74.
Koudova M, Seemanova E, Zenker M. Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. Eur J Med Genet. 2009;52(5):337–40.PubMedCrossRef
75.
Nishi E, Mizuno S, Nanjo Y, Niihori T, Fukushima Y, Matsubara Y, et al. A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. Am J Med Genet A. 2015;167A(2):407–11.PubMedCrossRef
76.
Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006;78(2):279–90.PubMedCrossRef
77.
Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006;281(10):6785–92.PubMedCrossRef
78.
Yu ZH, Zhang RY, Walls CD, Chen L, Zhang S, Wu L, et al. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry. 2014;53(25):4136–51.PubMedCrossRef
79.
Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P, et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol. 2007;100(4):736–41.PubMedCrossRef
80.
Limongelli G, Pacileo G, Russo MG, Sarkozy A, Felicetti M, Di Salvo G, et al. Severe, early onset hypertrophic cardiomyopathy in a family with LEOPARD syndrome. J Prenat Med. 2008;2(2):24–6.PubMedPubMedCentral
81.
Hahn A, Lauriol J, Thul J, Behnke-Hall K, Logeswaran T, Schanzer A, et al. Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog. Am J Med Genet A. 2015;167A(4):744–51.PubMedCrossRef
82.
83.
Tidyman WE, Rauen KA. Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway. Expert Rev Mol Med. 2008;10: e37.PubMedCrossRef
84.
Siwik ES, Zahka KG, Wiesner GL, Limwongse C. Cardiac disease in Costello syndrome. Pediatrics. 1998;101(4 Pt 1):706–9.PubMedCrossRef
85.
van Eeghen AM, van Gelderen I, Hennekam RC. Costello syndrome: report and review. Am J Med Genet. 1999;82(2):187–93.PubMedCrossRef
86.
Lin AE, Alexander ME, Colan SD, Kerr B, Rauen KA, Noonan J, et al. Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome. Am J Med Genet A. 2011;155A(3):486–507.PubMedCrossRef
87.
Rauen KA, Banerjee A, Bishop WR, Lauchle JO, McCormick F, McMahon M, et al. Costello and cardio-facio-cutaneous syndromes: moving toward clinical trials in RASopathies. Am J Med Genet C Semin Med Genet. 2011;157C(2):136–46.PubMedCrossRef
88.
Siegel DH, Mann JA, Krol AL, Rauen KA. Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development. Br J Dermatol. 2012;166(3):601–7.PubMedPubMedCentralCrossRef
89.
Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A, et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006;38(3):294–6.PubMedCrossRef
90.
Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006;311(5765):1287–90.PubMedCrossRef
91.
Ly KI, Blakeley JO. The diagnosis and management of neurofibromatosis type 1. Med Clin North Am. 2019;103(6):1035–54.PubMedCrossRef
92.
Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR et al. Health supervision for children with neurofibromatosis type 1. Pediatrics. 2019;143(5)
93.
Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123(1):124–33.PubMedCrossRef
94.
Cawthon RM, O’Connell P, Buchberg AM, Viskochil D, Weiss RB, Culver M, et al. Identification and characterization of transcripts from the neurofibromatosis 1 region: the sequence and genomic structure of EVI2 and mapping of other transcripts. Genomics. 1990;7(4):555–65.PubMedCrossRef
95.
Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990;62(1):187–92.PubMedCrossRef
96.
Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990;249(4965):181–6.PubMedCrossRef
97.
Bergoug M, Doudeau M, Godin F, Mosrin C, Vallee B, Benedetti H. Neurofibromin structure, functions and regulation. Cells. 2020;9(11)
98.
Viskochil D. Genetics of neurofibromatosis 1 and the NF1 gene. J Child Neurol. 2002;17(8):562–70 (discussion 71–2, 646–51).PubMedCrossRef
99.
Yunoue S, Tokuo H, Fukunaga K, Feng L, Ozawa T, Nishi T, et al. Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras. J Biol Chem. 2003;278(29):26958–69.PubMedCrossRef
100.
Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81–8.PubMedCrossRef
101.
Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, et al. Cardiovascular disease in neurofibromatosis 1: report of the NF1 cardiovascular task force. Genet Med. 2002;4(3):105–11.PubMedCrossRef
102.
Lin AE, Birch PH, Korf BR, Tenconi R, Niimura M, Poyhonen M, et al. Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1. Am J Med Genet. 2000;95(2):108–17.PubMedCrossRef
103.
Wilkinson JD, Lowe AM, Salbert BA, Sleeper LA, Colan SD, Cox GF, et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2012;164(3):442–8.PubMedCrossRef
104.
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–90.PubMedCrossRef
105.
106.
Lee S, Rauch J, Kolch W. Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity. Int J Mol Sci. 2020;21(3)
107.
Chen PC, Wakimoto H, Conner D, Araki T, Yuan T, Roberts A, et al. Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation. J Clin Invest. 2010;120(12):4353–65.PubMedPubMedCentralCrossRef
108.
Hernandez-Porras I, Fabbiano S, Schuhmacher AJ, Aicher A, Canamero M, Camara JA, et al. K-RasV14I recapitulates Noonan syndrome in mice. Proc Natl Acad Sci U S A. 2014;111(46):16395–400.PubMedPubMedCentralCrossRef
109.
Wu X, Simpson J, Hong JH, Kim KH, Thavarajah NK, Backx PH, et al. MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf 1(L613V) mutation. J Clin Invest. 2011;121(3):1009–25.PubMedPubMedCentralCrossRef
110.
Andelfinger G, Marquis C, Raboisson MJ, Theoret Y, Waldmuller S, Wiegand G, et al. Hypertrophic cardiomyopathy in Noonan syndrome treated by MEK-inhibition. J Am Coll Cardiol. 2019;73(17):2237–9.PubMedPubMedCentralCrossRef
111.
Sussman MA, Volkers M, Fischer K, Bailey B, Cottage CT, Din S, et al. Myocardial AKT: the omnipresent nexus. Physiol Rev. 2011;91(3):1023–70.PubMedCrossRef
112.
113.
Haq S, Choukroun G, Lim H, Tymitz KM, del Monte F, Gwathmey J, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation. 2001;103(5):670–7.PubMedCrossRef
114.
Luckey SW, Walker LA, Smyth T, Mansoori J, Messmer-Kratzsch A, Rosenzweig A, et al. The role of Akt/GSK-3beta signaling in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2009;46(5):739–47.PubMedPubMedCentralCrossRef
115.
Naga Prasad SV, Esposito G, Mao L, Koch WJ, Rockman HA. Gbetagamma-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy. J Biol Chem. 2000;275(7):4693–8.PubMedCrossRef
116.
Marin TM, Keith K, Davies B, Conner DA, Guha P, Kalaitzidis D, et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011;121(3):1026–43.PubMedPubMedCentralCrossRef
117.
Wang J, Chandrasekhar V, Abbadessa G, Yu Y, Schwartz B, Kontaridis MI. In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan syndrome with multiple lentigines-associated hypertrophic cardiomyopathy. PLoS ONE. 2017;12(6): e0178905.PubMedPubMedCentralCrossRef
118.
Paardekooper Overman J, Yi JS, Bonetti M, Soulsby M, Preisinger C, Stokes MP, et al. PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice. Mol Cell Biol. 2014;34(15):2874–89.PubMedPubMedCentralCrossRef
119.
Yi JS, Huang Y, Kwaczala AT, Kuo IY, Ehrlich BE, Campbell SG, et al. Low-dose dasatinib rescues cardiac function in Noonan syndrome. JCI Insight. 2016;1(20): e90220.PubMedPubMedCentralCrossRef
120.
Yi JS, Perla S, Huang Y, Mizuno K, Giordano FJ, Vinks AA et al. Low-dose dasatinib ameliorates hypertrophic cardiomyopathy in Noonan syndrome with multiple lentigines. Cardiovasc Drugs Ther. 2021
121.
122.
Gilbert BW. ACE inhibitors and regression of left ventricular hypertrophy. Clin Cardiol. 1992;15(10):711–4.PubMedCrossRef
123.
Schuhmacher AJ, Guerra C, Sauzeau V, Canamero M, Bustelo XR, Barbacid M. A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition. J Clin Invest. 2008;118(6):2169–79.PubMedPubMedCentral
124.
Tardiff JC, Carrier L, Bers DM, Poggesi C, Ferrantini C, Coppini R, et al. Targets for therapy in sarcomeric cardiomyopathies. Cardiovasc Res. 2015;105(4):457–70.PubMedPubMedCentralCrossRef
125.
Tsukamoto O. Direct sarcomere modulators are promising new treatments for cardiomyopathies. Int J Mol Sci. 2019;21(1)
126.
Zhu L, Roberts R, Huang R, Zhao J, Xia M, Delavan B, et al. Drug repositioning for Noonan and LEOPARD syndromes by integrating transcriptomics with a structure-based approach. Front Pharmacol. 2020;11:927.PubMedPubMedCentralCrossRef
127.
Carvajal-Vergara X, Sevilla A, D’Souza SL, Ang YS, Schaniel C, Lee DF, et al. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature. 2010;465(7299):808–12.PubMedPubMedCentralCrossRef
128.
Rooney GE, Goodwin AF, Depeille P, Sharir A, Schofield CM, Yeh E, et al. Human iPS cell-derived neurons uncover the impact of increased Ras signaling in Costello syndrome. J Neurosci. 2016;36(1):142–52.PubMedPubMedCentralCrossRef
129.
Yeh E, Dao DQ, Wu ZY, Kandalam SM, Camacho FM, Tom C, et al. Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment. Mol Psychiatry. 2018;23(8):1687–98.PubMedCrossRef
130.
Li R, Baskfield A, Lin Y, Beers J, Zou J, Liu C, et al. Generation of an induced pluripotent stem cell line (TRNDi003-A) from a Noonan syndrome with multiple lentigines (NSML) patient carrying a p.Q510P mutation in the PTPN11 gene. Stem Cell Res. 2019;34:101374.PubMedCrossRef
131.
Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med. 2004;10(8):849–57.PubMedCrossRef
132.
Nakamura T, Colbert M, Krenz M, Molkentin JD, Hahn HS, Dorn GW 2nd, et al. Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome. J Clin Invest. 2007;117(8):2123–32.PubMedPubMedCentralCrossRef
133.
Krenz M, Gulick J, Osinska HE, Colbert MC, Molkentin JD, Robbins J. Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome. Proc Natl Acad Sci U S A. 2008;105(48):18930–5.PubMedPubMedCentralCrossRef
134.
Yin JC, Platt MJ, Tian X, Wu X, Backx PH, Simpson JA, et al. Cellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome. Nat Commun. 2017;8:15518.PubMedPubMedCentralCrossRef
135.
Takahara S, Inoue SI, Miyagawa-Tomita S, Matsuura K, Nakashima Y, Niihori T, et al. New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to beta-adrenergic stimulation-induced cardiac fibrosis. EBioMedicine. 2019;42:43–53.PubMedPubMedCentralCrossRef
136.
Castel P, Cheng A, Cuevas-Navarro A, Everman DB, Papageorge AG, Simanshu DK, et al. RIT1 oncoproteins escape LZTR1-mediated proteolysis. Science. 2019;363(6432):1226–30.PubMedPubMedCentralCrossRef
137.
Steklov M, Pandolfi S, Baietti MF, Batiuk A, Carai P, Najm P, et al. Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science. 2018;362(6419):1177–82.PubMedPubMedCentralCrossRef
138.
Lauriol J, Cabrera JR, Roy A, Keith K, Hough SM, Damilano F, et al. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines. J Clin Invest. 2016;126(8):2989–3005.PubMedPubMedCentralCrossRef
139.
Tajan M, Batut A, Cadoudal T, Deleruyelle S, Le Gonidec S, Saint Laurent C, et al. LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity. Proc Natl Acad Sci U S A. 2014;111(42):E4494–503.PubMedPubMedCentralCrossRef
140.
Schramm C, Fine DM, Edwards MA, Reeb AN, Krenz M. The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling. Am J Physiol Heart Circ Physiol. 2012;302(1):H231–43.PubMedCrossRef
141.
Inoue S, Moriya M, Watanabe Y, Miyagawa-Tomita S, Niihori T, Oba D, et al. New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. Hum Mol Genet. 2014;23(24):6553–66.PubMedCrossRef
142.
Andreadi C, Cheung LK, Giblett S, Patel B, Jin H, Mercer K, et al. The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway. Genes Dev. 2012;26(17):1945–58.PubMedPubMedCentralCrossRef
143.
Aoidi R, Houde N, Landry-Truchon K, Holter M, Jacquet K, Charron L et al. Mek1(Y130C) mice recapitulate aspects of human cardio-facio-cutaneous syndrome. Dis Model Mech. 2018;11(3)
144.
Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 1994;8(9):1019–29.PubMedCrossRef
145.
Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet. 1994;7(3):353–61.PubMedCrossRef
146.
Gitler AD, Zhu Y, Ismat FA, Lu MM, Yamauchi Y, Parada LF, et al. Nf1 has an essential role in endothelial cells. Nat Genet. 2003;33(1):75–9.PubMedCrossRef
147.
Xu J, Ismat FA, Wang T, Lu MM, Antonucci N, Epstein JA. Cardiomyocyte-specific loss of neurofibromin promotes cardiac hypertrophy and dysfunction. Circ Res. 2009;105(3):304–11.PubMedPubMedCentralCrossRef
148.
Lee PA, Ross J, Germak JA, Gut R. Effect of 4 years of growth hormone therapy in children with Noonan syndrome in the American Norditropin Studies: Web-Enabled Research (ANSWER) Program(R) registry. Int J Pediatr Endocrinol. 2012;2012(1):15.PubMedPubMedCentralCrossRef
149.
Lee YS, Ehninger D, Zhou M, Oh JY, Kang M, Kwak C, et al. Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome. Nat Neurosci. 2014;17(12):1736–43.PubMedPubMedCentralCrossRef
150.
Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375(26):2550–60.PubMedPubMedCentralCrossRef
151.
Weiss BD, Wolters PL, Plotkin SR, Widemann BC, Tonsgard JH, Blakeley J, 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. 2021;39(7):797–806.PubMedPubMedCentralCrossRef
152.
Lion-Francois L, Gueyffier F, Mercier C, Gerard D, Herbillon V, Kemlin I, et al. The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial. Orphanet J Rare Dis. 2014;9:142.PubMedPubMedCentralCrossRef
153.
Robertson KA, Nalepa G, Yang FC, Bowers DC, Ho CY, Hutchins GD, et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol. 2012;13(12):1218–24.PubMedPubMedCentralCrossRef
Metadata
Title
An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies
Authors
Jae-Sung Yi
Sravan Perla
Anton M. Bennett
Publication date
14-02-2022
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 6/2023
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-022-07324-0

Other articles of this Issue 6/2023

Cardiovascular Drugs and Therapy 6/2023 Go to the issue

Review Article

Depletion of microRNA-92a Enhances the Role of Sevoflurane Treatment in Reducing Myocardial Ischemia–Reperfusion Injury by Upregulating KLF4

Review Article

Efficacy and Safety of Direct Oral Anticoagulants (DOACs) Versus Warfarin in Atrial Fibrillation Patients with Prior Stroke: a Systematic Review and Meta-analysis

Original Article

Preventive Effect of Bone Marrow Mononuclear Cell Transplantation on Acute Myocardial Infarction-Induced Heart Failure: A Meta-analysis of Randomized Controlled Trials

Review Article

An Updated Review on the Role of Non-dihydropyridine Calcium Channel Blockers and Beta-blockers in Atrial Fibrillation and Acute Decompensated Heart Failure: Evidence and Gaps

Short Communication

Rivaroxaban After Transcatheter Aortic Valve Replacement: A Critical Appraisal of the GALILEO Trial

Original Article

Non-VKA Oral Anticoagulants in Adult Congenital Heart Disease: a Single-Center Study