Targeting the “undruggable” RAS - new strategies - new hope?

Abstract

K-RAS is the most frequently mutated oncogene in solid tumors, such as pancreatic, colon or lung cancer. The GTPase K-RAS can either be in an active (GTP-loaded) or inactive (GDP-loaded) form. In its active form K-RAS forwards signals from growth factors, cytokines or hormones to the nucleus, regulating essential pathways, such as cell proliferation and differentiation. In turn, activating somatic mutations of this proto-oncogene deregulate the complex interplay between GAP (GTPase-activating) - and GEF (Guanine nucleotide exchange factor) - proteins, driving neoplastic transformation. Due to a rather shallow surface, K-RAS lacks proper binding pockets for small molecules, hindering drug development over the past thirty years. This review summarizes recent progress in the development of low molecular antagonists and further shows insights of a newly described interaction between mutant K-RAS signaling and PD-L1 induced immunosuppression, giving new hope for future treatments of K-RAS mutated cancer.

Keywords

K-RAS / small molecules / immune checkpoints / PD-1 / PD-L1

References

[1] Feig LA.Cell signaling: life or death decisions of Ras proteins..Curr Biol2002;12:259-61

[2] Shields JM,Shaub A.Understanding Ras : ‘it ain’t over ‘til it’s over’..Trends Cell Biol2000;10:147-54

[3] Bos JL.ras oncogenes in human cancer : a review..Cancer Res1989;49:4682-9

[4] Vetter IR.The guanine nucleotide - binding switch in three dimensions..Science2001;294:1299-304

[5] Lenzen C,Prinz H.Kinetic analysis by fluorescence of the interaction between Ras and the catalytic domain of the guanine nucleotide exchange factor Cdc25Mm..Biochemistry1998;37:7420-30

[6] Karnoub AE.Ras oncogenes: split personalities..Nat Rev Mol Cell Biol2008;9:517-31 PMCID:PMC3915522

[7] Vetter IR.The structure of the G domain of the Ras superfamily. Ras Superfamily Small G Proteins: Biology and Mechanisms 1.2014;WienSpringer Verlag25-51

[8] Wittinghofer A.Structure-function relationships of the G domain, a canonical switch motif..Ann Rev Biochem2011;80:943-71

[9] Spoerner M,Herrmann C,Kalbitzer HR.Slow conformational dynamics of the guanine nucleotide-binding protein Ras complexed with the GTP analogue GTPγS..FEBS J2007;274:1419-33

[10] Spoerner M,Poetzl JA,Ganser P.Conformational states of human rat sarcoma (Ras) protein complexed with its natural ligand GTP and their role for effector interaction and GTP hydrolysis..J Biol Chem2010;285:39768-78 PMCID:PMC3000958

[11] Ito Y,Iwahara J,Kamiya A.Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein..Biochemistry1997;36:9109-19

[12] Barbacid M.ras genes..Annu Rev Biochem1987;56:779-827

[13] Malumbres M.RAS oncogenes: the first 30 years..Nat Rev Cancer2003;3:459-65

[14] Vetter IR.The guanine nucleotide-binding switch in three dimensions..Science2001;294:1299-304

[15] Hancock JF.Ras proteins: different signals from different locations..Nat Rev Mol Cell Biol2003;4:373-84

[16] Lemmon MA.Cell signaling by receptor tyrosine kinases..Cell2010;141:1117-34 PMCID:PMC2914105

[17] Cox AD.Ras history: the saga continues..Small GTPases2010;1:2-27 PMCID:PMC3109476

[18] Gibbs JB,Poe M.Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules..Proc Natl Acad Sci U S A1984;81:5704-8 PMCID:PMC391779

[19] McGrath JP,Goeddel DV.Comparative biochemical properties of normal and activated human ras p21 protein..Nature1984;310:644-9

[20] Sweet RW,Kamata T,Rosenberg M.The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity..Nature1984;311:273-5

[21] Scheffzek K,Kabsch W,Wittinghofer A.Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras..Nature1996;384:591-6

[22] Schubbert S,Bollag G.Hyperactive Ras in developmental disorders and cancer..Nat Rev Cancer2007;7:295-308

[23] Jemal A,Xu J.Cancer statistics, 2010..CA Cancer J Clin2010;60:277-300

[24] Dhillon AS,Rath O.MAP kinase signalling pathways in cancer..Oncogene2007;26:3279-90

[25] De Luca A,D'Alessio A,Normanno N.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

[26] Pullikuth AK.Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: a perspective..Cell Signal2007;19:1621-32 PMCID:PMC2233890

[27] Ma L,Erdjument-Bromage H,Pandolfi PP.Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis..Cell2005;121:179-93

[28] Choi M,Mofunanya A.Challenges in Ras therapeutics in pancreatic cancer..Semin Cancer Biol2019;54:101-8

[29] Yang SH,Whitmarsh AJ.MAP kinase signalling cascades and transcriptional regulation..Gene2013;513:1-13

[30] Andjelkovic M,Meier R,Lamb NJ.Role of translocation in the activation and function of protein kinase B..J Biol Chem1997;272:31515-24

[31] Cai SL,Short JD,Kim J.Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning..J Cell Biol2006;173:279-89 PMCID:PMC2063818

[32] Long GV,Santinami M,Mandala M.Adjuvant Dabrafenib plus Trametinib in stage III BRAF-mutated melanoma..N Engl J Med2017;377:1813-23

[33] Janne PA,Barlesi F,Mazieres J.Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial..JAMA2017;317:1844-53 PMCID:PMC5815037

[34] Pulido JS,Marmorstein AD.Selumetinib in plexiform neurofibromas..N Engl J Med2017;376:1195

[35] Signorelli J.Cobimetinib..Ann Pharmacother2017;51:146-53

[36] Dummer R,Ascierto PA,Dutriaux C.Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial..Lancet Oncol2017;18:435-45

[37] Nijenhuis CM,Blank C,van Thienen JV.Clinical Pharmacokinetics of Vemurafenib in BRAF-mutated melanoma patients..J Clin Pharmacol2017;57:125-8

[38] Zhang W,Grippo JF.Clinical pharmacokinetics of vemurafenib..Clin Pharmacokinet2017;56:1033-43

[39] Delord JP,Nyakas M,Kudchakar R.Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma..Clin Cancer Res2017;23:5339-48

[40] Gounder MM,Van Tine BA,Attia S.Sorafenib for advanced and refractory desmoid tumors..N Engl J Med2018;379:2417-28 PMCID:PMC6447029

[41] Di Leo A,Lee KS,Lonning PE.Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial..Lancet Oncol2018;19:87-100

[42] Furman RR,Coutre SE,Pagel JM.Idelalisib and rituximab in relapsed chronic lymphocytic leukemia..N Engl J Med2014;370:997-1007

[43] Gopal AK,de Vos S,Schuster SJ.PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma..N Engl J Med2014;370:1008-18 PMCID:PMC4039496

[44] Younes A,Martinelli G,Barrigon DC.Pan-phosphatidylinositol 3-kinase inhibition with buparlisib in patients with relapsed or refractory non-Hodgkin lymphoma..Haematologica2017;102:2104-12 PMCID:PMC5709110

[45] Wang C,Xu X,Li H.Toward targeted therapy in chemotherapy-resistant pancreatic cancer with a smart triptolide nanomedicine..Oncotarget2016;7:8360-72 PMCID:PMC4884998

[46] Takai E.Genomic alterations in pancreatic cancer and their relevance to therapy..World J Gastrointest Oncol2015;7:250-8 PMCID:PMC4606179

[47] Grasso C,Giovannetti E.Drug resistance in pancreatic cancer: Impact of altered energy metabolism..Crit Rev Oncol Hematol2017;114:139-52

[48] Hezel AF,Stanger BZ,Depinho RA.Genetics and biology of pancreatic ductal adenocarcinoma..Genes Dev2006;20:1218-49

[49] Cetinbas NM,Harris RC,Negri GL.Glucose-dependent anaplerosis in cancer cells is required for cellular redox balance in the absence of glutamine..Sci Rep2016;6:32606 PMCID:PMC5015067

[50] Soleimani A,Rahsepar S,Bahrami A.Therapeutic potential of RAS prenylation pharmacological inhibitors in the treatment of breast cancer, recent progress, and prospective..J Cell Biochem2019;120:6860-7

[51] Whyte DB,Hockenberry TN,James L.K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors..J Biol Chem1997;272:14459-64

[52] Feuerstein J,John J,Wittinghofer A.Characterisation of the metal-ion-GDP complex at the active sites of transforming and nontransforming p21 proteins by observation of the 17O-Mn superhyperfine coupling and by kinetic methods..Eur J Biochem1987;162:49-55

[53] Traut TW.Physiological concentrations of purines and pyrimidines..Mol Cell Biochem1994;140:1-22

[54] Lim SM,Ficarro SB,Choi HG.Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor..Angew Chem Int Ed Engl2014;53:199-204 PMCID:PMC3914205

[55] Patricelli MP,Li LS,Peters U.Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state..Cancer Discov2016;6:316

[56] Ostrem JM,Sos ML,Shokat KM.K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions..Nature2013;503:548-51 PMCID:PMC4274051

[57] Patgiri A,Arora PS.An orthosteric inhibitor of Ras-Sos interaction..Nat Chem Biol2011;7:585-7 PMCID:PMC3312813

[58] Cochet O,Delumeau I,Multon MC.Intracellular Expression of an Antibody Fragment-neutralizing p21 Ras Promotes Tumor Regression..Cancer Research1998;58:1170

[59] Maurer T,Oh A,Anderson DJ.Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity..Proc Natl Acad Sci U S A2012;109:5299-304 PMCID:PMC3325706

[60] Sun Q,Phan J,Olejniczak ET.Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation..Angew Chem Int Ed Engl2012;51:6140-3 PMCID:PMC3620661

[61] Schöpel M,Seidel J,Zhong X.Allosteric activation of GDP-bound ras isoforms by bisphenol derivative plasticisers..Int J Mol Sci2018;19:1133 PMCID:PMC5979466

[62] Xie C,Li LL,Wang YW.Identification of a new potent inhibitor targeting KRAS in non-small cell lung cancer cells..Front Pharmacol2017;8:823 PMCID:PMC5694459

[63] Welsch ME,Chambers JM,Bos PH.Multivalent small-molecule Pan-RAS inhibitors..Cell2017;168:878-89.e29 PMCID:PMC5362268

[64] Quevedo CE,Bery N,Tanaka T.Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment..Nature communications2018;9:3169 PMCID:PMC6085350

[65] McCarthy MJ,Prakash P,van der Hoeven D.Discovery of high-affinity noncovalent allosteric KRAS inhibitors that disrupt effector binding..ACS Omega2019;4:2921-30 PMCID:PMC6396121

[66] Schöpel M,Düppe PM,Potheraveedu VN.Bisphenol a binds to Ras proteins and competes with guanine nucleotide exchange: implications for GTPase-selective antagonists..J Med Chem2013;56:9664-72

[67] Rogers JA,Yong VW.Review: endocrine disrupting chemicals and immune responses: a focus on bisphenol-A and its potential mechanisms..Mol Immunol2013;53:421-30

[68] Herr HW.History of bacillus calmette-guerin and bladder cancer: an immunotherapy success story..J Urol2008;179:53-6

[69] Balakrishnan AS,Meng MV.Determinants of guideline-based treatment in patients With cT1 bladder cancer..Clin Genitourin Cancer2019;17:e461-71

[70] Ishida Y,Shibahara K.Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death..EMBO J1992;11:3887-95 PMCID:PMC556898

[71] Xia Y,Young KH.Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies..Biochim Biophys Acta2016;1865:58-71 PMCID:PMC4733614

[72] Iwai Y,Honjo T.PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells..Int Immunol2005;17:133-44

[73] Gong J,Reddi S.Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations..J Immunother Cancer2018;6:8 PMCID:PMC5778665

[74] Hanahan D.Hallmarks of cancer: the next generation..Cell2011;144:646-74

[75] McKinney EF.T cell exhaustion and immune-mediated disease-the potential for therapeutic exhaustion..Curr Opin Immunol2016;43:74-80

[76] Garon EB,Hui R,Balmanoukian AS.Pembrolizumab for the treatment of non-small-cell lung cancer..N Engl J Med2015;372:2018-28

[77] Borghaei H,Horn L,Steins M.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer..N Engl J Med2015;373:1627-39 PMCID:PMC5705936

[78] Song TL,Laurensia Y,Tan J.Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma..Blood2018;132:1146-58 PMCID:PMC6148343

[79] Marzec M,Goradia A,Liu X.Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)..Proc Natl Acad Sci U S A2008;105:20852-7 PMCID:PMC2634900

[80] Atsaves V,Chioureas D,Leventaki V.PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma..Leukemia2017;31:1633-7

[81] Sumimoto H,Teramoto K.RAS-mitogen-activated protein kinase signal is required for enhanced PD-L1 expression in human lung cancers..PLoS One2016;11:e0166626 PMCID:PMC5112979

[82] Coelho MA,Rana S,Moore C.Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA..Immunity2017;47:1083-99.e6 PMCID:PMC5746170

[83] Jiang X,Giobbie-Hurder A,Hodi FS.The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition..Clin Cancer Res2013;19:598-609

[84] Sanlorenzo M,Floris A,Gammaitoni L.BRAF and MEK inhibitors increase PD-1-positive melanoma cells leading to a potential lymphocyte-independent synergism with anti-PD-1 antibody..Clin Cancer Res2018;24:3377-85

[85] Mittendorf EA,Meric-Bernstam F,Wu Y.PD-L1 expression in triple-negative breast cancer..Cancer Immunol Res2014;2:361-70

[86] Xu C,Koyama S,Zhao Y.Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression..Cancer Cell2014;25:590-604 PMCID:PMC4112370

[87] Lastwika KJ,Li QK,Xu H.Control of PD-L1 Expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer..Cancer Res2016;76:227-38

[88] Balan M,Waaga-Gasser AM,Choueiri TK.Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression..J Biol Chem2015;290:8110-20 PMCID:PMC4375468

[89] Wang Q,Peng H,Hou R.Tristetraprolin inhibits macrophage IL-27-induced activation of antitumour cytotoxic T cell responses..Nat Commun2017;8:867 PMCID:PMC5636828

[90] Kataoka K,Takeda Y,Matsumoto M.Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers..Nature2016;534:402-6

[91] Falk AT,Guibert N,Paquet A.Effect of mutant variants of the KRAS gene on PD-L1 expression and on the immune microenvironment and association with clinical outcome in lung adenocarcinoma patients..Lung Cancer2018;121:70-5

[92] Pallis M,Burrows F,Grundy M.The multi-kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells..Br J Haematol2012;159:191-203

[93] Goh KC,Hart S,Loh YK.TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties..Leukemia2012;26:236-43

[94] Su YT,Wang H,Zhang Q.Novel targeting of transcription and metabolism in glioblastoma..Clin Cancer Res2018;24:1124-37