Post-translational modification of KRAS: potential targets for cancer therapy

Abstract

Aberrant activation of the RAS superfamily is one of the critical factors in carcinogenesis. Among them, KRAS is the most frequently mutated one which has inspired extensive studies for developing approaches to intervention. Although the cognition toward KRAS remains far from complete, mounting evidence suggests that a variety of post-translational modifications regulate its activation and localization. In this review, we summarize the regulatory mode of post-translational modifications on KRAS including prenylation, post-prenylation, palmitoylation, ubiquitination, phosphorylation, SUMOylation, acetylation, nitrosylation, etc. We also highlight the recent studies targeting these modifications having exhibited potent anti-tumor activities.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: PTMsof KRAS proteins.
Fig. 2: PTMs regulate the activation and carcinogenesis of KRAS.

References

  1. 1.

    Cox AD, Der CJ. Ras history: the saga continues. Small GTPases. 2010;1:2–27.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Papke B, Der CJ. Drugging RAS: know the enemy. Science. 2017;355:1158–63.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001;294:1299–304.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170:17–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129:865–77.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer. 2010;10:842–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    NagDas SK, Winfrey VP, Olson GE. Identification of ras and its downstream signaling elements and their potential role in hamster sperm motility1. Biol Reprod. 2002;67:1058–66.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Ferro E, Trabalzini L. RalGDS family members couple Ras to Ral signalling and that’s not all. Cell Signal. 2010;22:1804–10.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    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;39:676–700.

    PubMed  Article  Google Scholar 

  10. 10.

    Prior IA, Hood FE, Hartley JL. The frequency of Ras mutations in cancer. Cancer Res. 2020;80:2969–74.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25:620–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129:1287–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Disco. 2014;13:828–51.

    CAS  Article  Google Scholar 

  15. 15.

    Lazo JS, Sharlow ER. Drugging undruggable molecular cancer targets. Annu Rev Pharmacol Toxicol. 2016;56:23–40.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Merchant M, Moffat J, Schaefer G, Chan J, Wang X, Orr C, et al. Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors. PLoS One. 2017;12:e0185862.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503:548–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Wang T, Yu H, Hughes NW, Liu B, Kendirli A, Klein K, et al. Gene essentiality profiling reveals gene networks and synthetic lethal interactions with oncogenic ras. Cell. 2017;168:890–903.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG. Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Disco. 2007;6:541–55.

    CAS  Article  Google Scholar 

  20. 20.

    Michael JV, Goldfinger LE. Concepts and advances in cancer therapeutic vulnerabilities in RAS membrane targeting. Semin Cancer Biol. 2019;54:121–30.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Liu P, Wang Y, Li X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm Sin B. 2019;9:871–9.

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Wright LP, Philips MR. Thematic review series: lipid posttranslational modifications. CAAX modification and membrane targeting of Ras. J Lipid Res. 2006;47:883–91.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Seabra MC, Reiss Y, Casey PJ, Brown MS, Goldstein JL. Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit. Cell. 1991;65:429–34.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Fu HW, Casey PJ. Enzymology and biology of CaaX protein prenylation. Recent Prog Horm Res. 1999;54:315–42. Discussion 42–3.

    CAS  PubMed  Google Scholar 

  25. 25.

    Reid TS, Terry KL, Casey PJ, Beese LS. Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity. J Mol Biol. 2004;343:417–33.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Berg TJ, Gastonguay AJ, Lorimer EL, Kuhnmuench JR, Li R, Fields AP, et al. Splice variants of SmgGDS control small GTPase prenylation and membrane localization. J Biol Chem. 2010;285:35255–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Garcia-Torres D, Fierke CA. The chaperone SmgGDS-607 has a dual role, both activating and inhibiting farnesylation of small GTPases. J Biol Chem. 2019;294:11793–804.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Siprashvili Z, Webster DE, Johnston D, Shenoy RM, Ungewickell AJ, Bhaduri A, et al. The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer. Nat Genet. 2016;48:53–8.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Dai X, Xia H, Zhou S, Tang Q, Bi F. Zoledronic acid enhances the efficacy of the MEK inhibitor trametinib in KRAS mutant cancers. Cancer Lett. 2019;442:202–12.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Dharmaiah S, Bindu L, Tran TH, Gillette WK, Frank PH, Ghirlando R, et al. Structural basis of recognition of farnesylated and methylated KRAS4b by PDEdelta. Proc Natl Acad Sci U S A. 2016;113:6766–75.

    Article  CAS  Google Scholar 

  31. 31.

    Papke B, Murarka S, Vogel HA, Martin-Gago P, Kovacevic M, Truxius DC, et al. Identification of pyrazolopyridazinones as PDEdelta inhibitors. Nat Commun. 2016;7:11360.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ, et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem. 1997;272:14459–64.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Otto JC, Kim E, Young SG, Casey PJ. Cloning and characterization of a mammalian prenyl protein-specific protease. J Biol Chem. 1999;274:8379–82.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Manolaridis I, Kulkarni K, Dodd RB, Ogasawara S, Zhang Z, Bineva G, et al. Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1. Nature. 2013;504:301–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Hancock JF, Cadwallader K, Marshall CJ. Methylation and proteolysis are essential for efficient membrane binding of prenylated p21K-ras(B). EMBO J. 1991;10:641–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Hancock JF, Paterson H, Marshall CJ. A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell. 1990;63:133–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Silvius JR, Bhagatji P, Leventis R, Terrone D. K-ras4B and prenylated proteins lacking “second signals” associate dynamically with cellular membranes. Mol Biol Cell. 2006;17:192–202.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Tsai FD, Lopes MS, Zhou M, Court H, Ponce O, Fiordalisi JJ, et al. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc Natl Acad Sci U S A. 2015;112:779–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Laude AJ, Prior IA. Palmitoylation and localisation of RAS isoforms are modulated by the hypervariable linker domain. J Cell Sci. 2008;121:421–7.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Shahinian S, Silvius JR. Doubly-lipid-modified protein sequence motifs exhibit long-lived anchorage to lipid bilayer membranes. Biochemistry. 1995;34:3813–22.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Schroeder H, Leventis R, Rex S, Schelhaas M, Nagele E, Waldmann H, et al. S-Acylation and plasma membrane targeting of the farnesylated carboxyl-terminal peptide of N-ras in mammalian fibroblasts. Biochemistry. 1997;36:13102–9.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Mitchell DA, Vasudevan A, Linder ME, Deschenes RJ. Protein palmitoylation by a family of DHHC protein S-acyltransferases. J Lipid Res. 2006;47:1118–27.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Swarthout JT, Lobo S, Farh L, Croke MR, Greentree WK, Deschenes RJ, et al. DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras. J Biol Chem. 2005;280:31141–8.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Rocks O, Gerauer M, Vartak N, Koch S, Huang ZP, Pechlivanis M, et al. The palmitoylation machinery is a spatially organizing system for peripheral membrane proteins. Cell. 2010;141:458–71.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Duncan JA, Gilman AG. A cytoplasmic acyl-protein thioesterase that removes palmitate from G protein alpha subunits and p21(RAS). J Biol Chem. 1998;273:15830–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Rusch M, Zimmermann TJ, Burger M, Dekker FJ, Gormer K, Triola G, et al. Identification of acyl protein thioesterases 1 and 2 as the cellular targets of the Ras-signaling modulators palmostatin B and M. Angew Chem Int Ed Engl. 2011;50:9838–42.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Ahearn IM, Tsai FD, Court H, Zhou M, Jennings BC, Ahmed M, et al. FKBP12 binds to acylated H-ras and promotes depalmitoylation. Mol Cell. 2011;41:173–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Tabaczar S, Czogalla A, Podkalicka J, Biernatowska A, Sikorski AF. Protein palmitoylation: palmitoyltransferases and their specificity. Exp Biol Med. 2017;242:1150–7.

    CAS  Article  Google Scholar 

  49. 49.

    McLaughlin S, Aderem A. The myristoyl-electrostatic switch: a modulator of reversible protein-membrane interactions. Trends Biochem Sci. 1995;20:272–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Cho KJ, Casteel DE, Prakash P, Tan L, van der Hoeven D, Salim AA, et al. AMPK and endothelial nitric oxide synthase signaling regulates K-Ras plasma membrane interactions via cyclic GMP-dependent protein kinase 2. Mol Cell Biol. 2016;36:3086–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Sung PJ, Tsai FD, Vais H, Court H, Yang J, Fehrenbacher N, et al. Phosphorylated K-Ras limits cell survival by blocking Bcl-xL sensitization of inositol trisphosphate receptors. Proc Natl Acad Sci U S A. 2013;110:20593–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Wang MT, Holderfield M, Galeas J, Delrosario R, To MD, Balmain A, et al. K-Ras promotes tumorigenicity through suppression of non-canonical Wnt signaling. Cell. 2015;163:1237–51.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Barcelo C, Paco N, Morell M, Alvarez-Moya B, Bota-Rabassedas N, Jaumot M, et al. Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth. Cancer Res. 2014;74:1190–9.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Yang MH, Nickerson S, Kim ET, Liot C, Laurent G, Spang R, et al. Regulation of RAS oncogenicity by acetylation. Proc Natl Acad Sci U S A. 2012;109:10843–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Baker R, Wilkerson EM, Sumita K, Isom DG, Sasaki AT, Dohlman HG, et al. Differences in the regulation of K-Ras and H-Ras isoforms by monoubiquitination. J Biol Chem. 2013;288:36856–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Yang MH, Laurent G, Bause AS, Spang R, German N, Haigis MC, et al. HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS. Mol Cancer Res. 2013;11:1072–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Song HY, Biancucci M, Kang HJ, O’Callaghan C, Park SH, Principe DR, et al. SIRT2 deletion enhances KRAS-induced tumorigenesis in vivo by regulating K147 acetylation status. Oncotarget. 2016;7:80336–49.

    PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Dharmaiah S, Tran TH, Messing S, Agamasu C, Gillette WK, Yan W, et al. Structures of N-terminally processed KRAS provide insight into the role of N-acetylation. Sci Rep. 2019;9:10512.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. 59.

    Lander HM, Ogiste JS, Teng KK, Novogrodsky A. p21ras as a common signaling target of reactive free radicals and cellular redox stress. J Biol Chem. 1995;270:21195–8.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Lander HM, Ogiste JS, Pearce SF, Levi R, Novogrodsky A. Nitric oxide-stimulated guanine nucleotide exchange on p21ras. J Biol Chem. 1995;270:7017–20.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Lander HM, Hajjar DP, Hempstead BL, Mirza UA, Chait BT, Campbell S, et al. A molecular redox switch on p21(ras). Structural basis for the nitric oxide-p21(ras) interaction. J Biol Chem. 1997;272:4323–6.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Lee M, Choy JC. Positive feedback regulation of human inducible nitric-oxide synthase expression by Ras protein S-nitrosylation. J Biol Chem. 2013;288:15677–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Lim K-H, Ancrile BB, Kashatus DF, Counter CM. Tumour maintenance is mediated by eNOS. Nature. 2008;452:646–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Mansour M. Ubiquitination: friend and foe in cancer. Int J Biochem Cell Biol. 2018;101:80–93.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Sasaki AT, Carracedo A, Locasale JW, Anastasiou D, Takeuchi K, Kahoud ER, et al. Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors. Sci Signal. 2011;4:ra13.

    PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Yin G, Kistler S, George SD, Kuhlmann N, Garvey L, Huynh M, et al. A KRAS GTPase K104Q mutant retains downstream signaling by offsetting defects in regulation. J Biol Chem. 2017;292:4446–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Bigenzahn JW, Collu GM, Kartnig F, Pieraks M, Vladimer GI, Heinz LX, et al. LZTR1 is a regulator of RAS ubiquitination and signaling. Science. 2018;362:1171–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Yu B, Swatkoski S, Holly A, Lee LC, Giroux V, Lee CS, et al. Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9. Proc Natl Acad Sci U S A. 2015;112:1724–33.

    Article  CAS  Google Scholar 

  69. 69.

    Choi BH, Philips MR, Chen Y, Lu L, Dai W. K-Ras Lys-42 is crucial for its signaling, cell migration, and invasion. J Biol Chem. 2018;293:17574–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Choi BH, Chen C, Philips M, Dai W. RAS GTPases are modified by SUMOylation. Oncotarget. 2018;9:4440–50.

    PubMed  Article  Google Scholar 

  71. 71.

    Kano Y, Gebregiworgis T, Marshall CB, Radulovich N, Poon BPK, St-Germain J, et al. Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation. Nat Commun. 2019;10:224.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Ruess DA, Heynen GJ, Ciecielski KJ, Ai J, Berninger A, Kabacaoglu D, et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med. 2018;24:954–60.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Barcelo C, Paco N, Beckett AJ, Alvarez-Moya B, Garrido E, Gelabert M, et al. Oncogenic K-ras segregates at spatially distinct plasma membrane signaling platforms according to its phosphorylation status. J Cell Sci. 2013;126:4553–9.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Sumita K, Yoshino H, Sasaki M, Majd N, Kahoud ER, Takahashi H, et al. Degradation of activated K-Ras orthologue via K-Ras-specific lysine residues is required for cytokinesis. J Biol Chem. 2014;289:3950–9.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Zeng T, Wang Q, Fu J, Lin Q, Bi J, Ding W, et al. Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis. Cell Rep. 2014;7:871–82.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Baietti MF, Simicek M, Abbasi Asbagh L, Radaelli E, Lievens S, Crowther J, et al. OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination. EMBO Mol Med. 2016;8:288–303.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Shukla S, Allam US, Ahsan A, Chen G, Krishnamurthy PM, Marsh K, et al. KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated beta-TrCP1 degradation. Neoplasia. 2014;16:115–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Li H, Tan M, Jia L, Wei D, Zhao Y, Chen G, et al. Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis. J Clin Invest. 2014;124:835–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Xie C-M, Wei D, Zhao L, Marchetto S, Mei L, Borg J-P, et al. Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates KrasG12D-induced skin tumorigenesis. J Cell Biol. 2015;209:721–37.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Tan M, Xu J, Siddiqui J, Feng F, Sun Y. Depletion of SAG/RBX2 E3 ubiquitin ligase suppresses prostate tumorigenesis via inactivation of the PI3K/AKT/mTOR axis. Mol Cancer. 2016;15:81. https://doi.org/10.1186/s12943-016-0567-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Aktories K. Bacterial protein toxins that modify host regulatory GTPases. Nat Rev Microbiol. 2011;9:487–98.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Just I, Selzer J, Hofmann F, Green GA, Aktories K. Inactivation of Ras by Clostridium sordellii lethal toxin-catalyzed glucosylation. J Biol Chem. 1996;271:10149–53.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Genth H, Just I. Functional implications of lethal toxin-catalysed glucosylation of (H/K/N)Ras and Rac1 in Clostridium sordellii-associated disease. Eur J Cell Biol. 2011;90:959–65.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Ganesan AK, Vincent TS, Olson JC, Barbieri JT. Pseudomonas aeruginosa exoenzyme S disrupts Ras-mediated signal transduction by inhibiting guanine nucleotide exchange factor-catalyzed nucleotide exchange. J Biol Chem. 1999;274:21823–9.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Kato K, Cox AD, Hisaka MM, Graham SM, Buss JE, Der CJ. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A. 1992;89:6403–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Basso AD, Kirschmeier P, Bishop WR. Lipid posttranslational modifications. Farnesyl transferase inhibitors. J Lipid Res. 2006;47:15–31.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Alcock RA, Dey S, Chendil D, Inayat MS, Mohiuddin M, Hartman G, et al. Farnesyltransferase inhibitor (L-744,832) restores TGF-β type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2. Oncogene. 2002;21:7883–90.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Mendes J, Gonçalves AC, Alves R, Jorge J, Pires A, Ribeiro A, et al. L744,832 and everolimus induce cytotoxic and cytostatic effects in non-Hodgkin lymphoma cells. Pathol Oncol Res. 2016;22:301–9.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Marin-Ramos NI, Ortega-Gutierrez S, Lopez-Rodriguez ML. Blocking Ras inhibition as an antitumor strategy. Semin Cancer Biol. 2019;54:91–100.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9:517–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Liu M, Sjogren AK, Karlsson C, Ibrahim MX, Andersson KM, Olofsson FJ, et al. Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer. Proc Natl Acad Sci U S A. 2010;107:6471–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Lobell RB, Liu D, Buser CA, Davide JP, DePuy E, Hamilton K, et al. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther. 2002;1:747–58.

    CAS  PubMed  Google Scholar 

  93. 93.

    Du W, Prendergast GC. Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res. 1999;59:5492–6.

    CAS  PubMed  Google Scholar 

  94. 94.

    Subramani PA, Narala VR, Michael RD, Lomada D, Reddy MC. Molecular docking and simulation of curcumin with geranylgeranyl transferase1 (GGTase1) and farnesyl transferase (FTase). Bioinformation. 2015;11:248–53.

    PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Kazi A, Xiang S, Yang H, Chen L, Kennedy P, Ayaz M, et al. Dual farnesyl and geranylgeranyl transferase inhibitor thwarts mutant KRAS-driven patient-derived pancreatic tumors. Clin Cancer Res. 2019;25:5984–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241–69.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Demierre M-F, Higgins PDR, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer. 2005;5:930–42.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Wong WW, Dimitroulakos J, Minden MD, Penn LZ. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002;16:508–19.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Yu R, Longo J, van Leeuwen JE, Mullen PJ, Ba-Alawi W, Haibe-Kains B, et al. Statin-induced cancer cell death can be mechanistically uncoupled from prenylation of RAS family proteins. Cancer Res. 2018;78:1347–57.

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Senaratne SG, Mansi JL, Colston KW. The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells. Br J Cancer. 2002;86:1479–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360:679–91.

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Jahnke W, Rondeau J-M, Cotesta S, Marzinzik A, Pellé X, Geiser M, et al. Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery. Nat Chem Biol. 2010;6:660–6.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Winter-Vann AM, Casey PJ. Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer. 2005;5:405–12.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Bergo MO, Wahlstrom AM, Fong LG, Young SG. Genetic analyses of the role of RCE1 in RAS membrane association and transformation. Methods Enzymol. 2008;438:367–89.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Bergo MO, Ambroziak P, Gregory C, George A, Otto JC, Kim E, et al. Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol Cell Biol. 2002;22:171–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Bergo MO, Gavino BJ, Hong C, Beigneux AP, McMahon M, Casey PJ, et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J Clin Invest. 2004;113:539–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Manandhar SP, Hildebrandt ER, Jacobsen WH, Santangelo GM, Schmidt WK. Chemical inhibition of CaaX protease activity disrupts yeast Ras localization. Yeast. 2010;27:327–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Mohammed I, Hampton SE, Ashall L, Hildebrandt ER, Kutlik RA, Manandhar SP, et al. 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. Bioorg Med Chem. 2016;24:160–78.

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Bergo MO, Lieu HD, Gavino BJ, Ambroziak P, Otto JC, Casey PJ, et al. On the physiological importance of endoproteolysis of CAAX proteins: heart-specific RCE1 knockout mice develop a lethal cardiomyopathy. J Biol Chem. 2004;279:4729–36.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Aiyagari AL, Taylor BR, Aurora V, Young SG, Shannon KM. Hematologic effects of inactivating the Ras processing enzyme Rce1. Blood. 2003;101:2250–2.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Marin-Ramos NI, Balabasquer M, Ortega-Nogales FJ, Torrecillas IR, Gil-Ordonez A, Marcos-Ramiro B, et al. A potent isoprenylcysteine carboxylmethyltransferase (ICMT) inhibitor improves survival in Ras-driven acute myeloid leukemia. J Med Chem. 2019;62:6035–46.

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Shi YQ, Rando RR. Kinetic mechanism of isoprenylated protein methyltransferase. J Biol Chem. 1992;267:9547–51.

    CAS  PubMed  Google Scholar 

  113. 113.

    Diver MM, Pedi L, Koide A, Koide S, Long SB. Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT. Nature. 2018;553:526–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Wnuk SF, Yuan CS, Borchardt RT, Balzarini J, De Clercq E, Robins MJ. Anticancer and antiviral effects and inactivation of S-adenosyl-L-homocysteine hydrolase with 5ʼ-carboxaldehydes and oximes synthesized from adenosine and sugar-modified analogues. J Med Chem. 1997;40:1608–18.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Winter-Vann AM, Kamen BA, Bergo MO, Young SG, Melnyk S, James SJ, et al. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc Natl Acad Sci U S A. 2003;100:6529–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Bergman JA, Hahne K, Song J, Hrycyna CA, Gibbs RA. S-Farnesyl-thiopropionic acid triazoles as potent inhibitors of isoprenylcysteine carboxyl methyltransferase. ACS Med Chem Lett. 2012;3:15–9.

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Wang M, Tan W, Zhou J, Leow J, Go M, Lee HS, et al. A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J Biol Chem. 2008;283:18678–84.

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Winter-Vann AM, Baron RA, Wong W, dela Cruz J, York JD, Gooden DM, et al. A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc Natl Acad Sci U S A. 2005;102:4336–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Lau HY, Ramanujulu PM, Guo D, Yang T, Wirawan M, Casey PJ, et al. An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol Ther. 2014;15:1280–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Chiu VK, Bivona T, Hach A, Sajous JB, Silletti J, Wiener H, et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nat Cell Biol. 2002;4:343–50.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Lin DTS, Davis NG, Conibear E. Targeting the Ras palmitoylation/depalmitoylation cycle in cancer. Biochem Soc Trans. 2017;45:913–21.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Amendola CR, Mahaffey JP, Parker SJ, Ahearn IM, Chen W-C, Zhou M, et al. KRAS4A directly regulates hexokinase 1. Nature. 2019;576:482–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C, et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol. 2011;7:523.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. 124.

    Hu CM, Tien SC, Hsieh PK, Jeng YM, Chang MC, Chang YT, et al. High glucose triggers nucleotide imbalance through O-GlcNAcylation of key enzymes and induces KRAS mutation in pancreatic cells. Cell Metab. 2019;29:1334–49.e10.

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Taparra K, Wang H, Malek R, Lafargue A, Barbhuiya MA, Wang X, et al. O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis. J Clin Invest. 2018;128:4924–37.

    PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Nandi D, Tahiliani P, Kumar A, Chandu D. The ubiquitin-proteasome system. J Biosci. 2006;31:137–55.

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Sun Y. E3 ubiquitin ligases as cancer targets and biomarkers. Neoplasia. 2006;8:645–54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Senft D, Qi J. Ronai ZeA. Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer. 2018;18:69–88.

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Jeong WJ, Park JC, Kim WS, Ro EJ, Jeon SH, Lee SK, et al. WDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation. Nat Commun. 2019;10:295.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130.

    Ma Y, Gu Y, Zhang Q, Han Y, Yu S, Lu Z, et al. Targeted degradation of KRAS by an engineered ubiquitin ligase suppresses pancreatic cancer cell growth in vitro and in vivo. Mol Cancer Ther. 2013;12:286–94.

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Pan T, Zhang Y, Zhou N, He X, Chen C, Liang L, et al. A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth. Oncotarget. 2016;7:44299–309.

    PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, et al. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-Xl on mitochondria and induces apoptosis. Mol Cell. 2006;21:481–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Becher I, Savitski MM, Savitski MF, Hopf C, Bantscheff M, Drewes G. Affinity profiling of the cellular kinome for the nucleotide cofactors ATP, ADP, and GTP. ACS Chem Biol. 2013;8:599–607.

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction. Proc Natl Acad Sci U S A. 2019;116:2551–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Maurer T, Garrenton LS, Oh A, Pitts K, Anderson DJ, Skelton NJ, et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci U S A. 2012;109:5299–304.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Gehringer M, Laufer SA. Emerging and re-emerging warheads for targeted covalent inhibitors: applications in medicinal chemistry and chemical biology. J Med Chem. 2019;62:5673–724.

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Fakih M, O’Neil B, Price TJ, Falchook GS, Desai J, Kuo J, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors (Abstract). J Clin Oncol. 2019;37:3003.

    Article  Google Scholar 

  138. 138.

    Papadopoulos KP, Ou S-HI, Johnson ML, Christensen J, Velastegui K, Potvin D, et al. A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation. J Clin Oncol. 2019;37:TPS3161–TPS61.

    Article  Google Scholar 

  139. 139.

    Janes MR, Zhang J, Li L-S, Hansen R, Peters U, Guo X, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172:578–89.e17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Bar-Sagi D, Knelson EH, Sequist LV. A bright future for KRAS inhibitors. Nat Cancer. 2020;1:25–7.

    Article  Google Scholar 

  141. 141.

    Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pr. 2009;205:858–62.

    CAS  Article  Google Scholar 

  142. 142.

    Scheffler M, Ihle MA, Hein R, Merkelbach-Bruse S, Scheel AH, Siemanowski J, et al. K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways. J Thorac Oncol. 2019;14:606–16.

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition. Clin Cancer Res. 2020;26:1633–43.

    PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Jin-jian Lu or Hong Zhu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, Wh., Yuan, T., Qian, Mj. et al. Post-translational modification of KRAS: potential targets for cancer therapy. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-00542-y

Download citation

Keywords

  • oncogene
  • KRAS
  • post-translational modification
  • prenylation
  • postprenylation
  • palmitoylation
  • ubiquitination
  • phosphorylation
  • SUMOylation
  • acetylation
  • nitrosylation
  • cancer therapy

Search