Abstract
The occurrence of somatic substitution mutations of the KRAS proto-oncogene is highly prevalent in certain cancer types, which often leads to constant activation of proliferative pathways and subsequent neoplastic transformation. It is often seen as a gateway mutation in carcinogenesis and has been commonly deemed as a predictive biomarker for poor prognosis and relapse when conventional chemotherapeutics are employed. Additionally, its mutational status also renders EGFR targeted therapies ineffective owing to its downstream location. Efforts to discover new approaches targeting this menacing culprit have been ongoing for years without much success, and with incidences of KRAS positive cancer patients being on the rise, researchers are now turning towards immunotherapies as the way forward. In this scoping review, recent immunotherapeutic developments and advances in both preclinical and clinical studies targeting K-ras directly or indirectly via its downstream signal transduction machinery will be discussed. Additionally, some of the challenges and limitations of various K-ras targeting immunotherapeutic approaches such as vaccines, adoptive T cell therapies, and checkpoint inhibitors against KRAS positive cancers will be deliberated.
Keywords: KRAS mutation, Cancer, Immunotherapies, Targeted therapies, Cancer vaccines, RTK.
[http://dx.doi.org/10.1177/1947601911411084] [PMID: 21779504]
[http://dx.doi.org/10.1242/jcs.182873] [PMID: 26985062]
[http://dx.doi.org/10.14744/ejmo.2017.22931]
[http://dx.doi.org/10.1038/nrd4389] [PMID: 25323927]
[PMID: 20680106]
[http://dx.doi.org/10.2478/s11535-013-0158-5]
[http://dx.doi.org/10.1155/2010/150960] [PMID: 20617134]
[http://dx.doi.org/10.1016/j.cell.2017.06.009] [PMID: 28666118]
[http://dx.doi.org/10.3390/cancers8040045] [PMID: 27096871]
[http://dx.doi.org/10.1016/j.ajme.2014.01.003]
[PMID: 24068405]
[http://dx.doi.org/10.1097/PDM.0b013e3181c93fd1] [PMID: 20736745]
[PMID: 25450577]
[http://dx.doi.org/10.1093/annonc/mdq680] [PMID: 21169473]
[http://dx.doi.org/10.1186/s13046-018-0719-1] [PMID: 29534749]
[http://dx.doi.org/10.1053/j.gastro.2013.01.071] [PMID: 23622131]
[PMID: 23066310]
[http://dx.doi.org/10.1038/onc.2017.377] [PMID: 29059163]
[http://dx.doi.org/10.1056/NEJMoa1011923] [PMID: 21561347]
[http://dx.doi.org/10.1056/NEJMoa1304369] [PMID: 24131140]
[http://dx.doi.org/10.1097/JTO.0b013e3181c6f035] [PMID: 20101151]
[http://dx.doi.org/10.4137/BCBCR.S32783] [PMID: 27042088]
[http://dx.doi.org/10.1001/jama.2011.51] [PMID: 21285426]
[http://dx.doi.org/10.4238/2014.July.25.9] [PMID: 25117311]
[http://dx.doi.org/10.2217/pgs.11.118] [PMID: 22118052]
[http://dx.doi.org/10.1016/j.clbc.2014.10.006] [PMID: 25441421]
[http://dx.doi.org/10.5306/wjco.v8.i2.120] [PMID: 28439493]
[http://dx.doi.org/10.1592/phco.28.11-supp.23S] [PMID: 18980549]
[http://dx.doi.org/10.1097/JTO.0b013e3181da36f4] [PMID: 20686429]
[http://dx.doi.org/10.1200/JCO.2008.16.2412] [PMID: 19224857]
[http://dx.doi.org/10.1016/j.lungcan.2018.07.013] [PMID: 30268480]
[http://dx.doi.org/10.1186/s12943-018-0789-x] [PMID: 29455666]
[http://dx.doi.org/10.3390/cancers10020036] [PMID: 29382159]
[http://dx.doi.org/10.1007/s00428-008-0665-y] [PMID: 18802721]
[http://dx.doi.org/10.1186/1878-5085-4-3] [PMID: 23356214]
[http://dx.doi.org/10.5009/gnl15465] [PMID: 27114434]
[http://dx.doi.org/10.3390/ijms18040752] [PMID: 28368335]
[http://dx.doi.org/10.1200/JCO.2009.21.9618] [PMID: 20100966]
[http://dx.doi.org/10.1016/S0140-6736(09)60569-9] [PMID: 19410716]
[http://dx.doi.org/10.1016/S1470-2045(12)70087-6] [PMID: 22452896]
[PMID: 23997942]
[http://dx.doi.org/10.1371/journal.pone.0187289] [PMID: 29088281]
[http://dx.doi.org/10.1007/s10637-012-9818-6] [PMID: 22547163]
[http://dx.doi.org/10.2217/fon.10.71] [PMID: 20528225]
[http://dx.doi.org/10.1016/j.ejca.2014.04.024] [PMID: 24915778]
[http://dx.doi.org/10.1016/j.canlet.2016.12.035] [PMID: 28093284]
[http://dx.doi.org/10.1038/nrd.2016.139] [PMID: 27469033]
[http://dx.doi.org/10.1158/2159-8290.CD-15-1105] [PMID: 26739882]
[http://dx.doi.org/10.1126/science.aad6204] [PMID: 26841430]
[PMID: 25806345]
[http://dx.doi.org/10.1038/nm.1890] [PMID: 19029981]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-3728] [PMID: 24675361]
[http://dx.doi.org/10.1016/j.ccr.2012.11.007] [PMID: 23245996]
[http://dx.doi.org/10.1158/2159-8290.CD-12-0446] [PMID: 23454899]
[http://dx.doi.org/10.1038/nrc.2017.79] [PMID: 28984291]
[http://dx.doi.org/10.4161/hv.19795] [PMID: 22832254]
[http://dx.doi.org/10.1016/B978-0-12-374279-7.17020-1]
[http://dx.doi.org/10.1586/14760584.3.4.349] [PMID: 15270632]
[http://dx.doi.org/10.4161/hv.5.10.9518] [PMID: 19684472]
[http://dx.doi.org/10.1038/nrc3153] [PMID: 22020206]
[http://dx.doi.org/10.1016/S1470-2045(17)30607-1] [PMID: 29208439]
[http://dx.doi.org/10.1038/nri.2017.145] [PMID: 29332937]
[http://dx.doi.org/10.7150/jca.24577] [PMID: 29805703]
[http://dx.doi.org/10.1038/s41573-018-0006-z] [PMID: 30622344]
[PMID: 23725603]
[http://dx.doi.org/10.1038/nrclinonc.2014.111] [PMID: 25001465]
[http://dx.doi.org/10.1007/s12282-016-0688-1] [PMID: 27000871]
[http://dx.doi.org/10.1016/j.cell.2018.09.035] [PMID: 30290139]
[http://dx.doi.org/10.1186/1479-5876-12-141] [PMID: 24886164]
[http://dx.doi.org/10.2217/imt.14.86] [PMID: 25524383]
[http://dx.doi.org/10.1073/pnas.1508516112] [PMID: 26598681]
[http://dx.doi.org/10.1097/PPO.0b013e318233e5b2] [PMID: 21952285]
[http://dx.doi.org/10.4161/onci.23403] [PMID: 23802081]
[http://dx.doi.org/10.4161/21645515.2014.983000] [PMID: 25625923]
[http://dx.doi.org/10.1186/s12916-016-0623-5] [PMID: 27151159]
[http://dx.doi.org/10.1177/003335491613100216] [PMID: 26957667]
[http://dx.doi.org/10.7150/jca.20059] [PMID: 29344272]
[http://dx.doi.org/10.4236/ojmm.2014.43020]
[http://dx.doi.org/ 10.3892/ijmm.2014.2000] [PMID: 25395173]
[http://dx.doi.org/10.24294/ti.v1.i1.41]
[http://dx.doi.org/10.1080/23808993.2017.1403286]
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1322] [PMID: 20940398]
[http://dx.doi.org/10.1038/nature03337] [PMID: 15744305]
[http://dx.doi.org/10.1084/jem.20091918] [PMID: 20156971]
[http://dx.doi.org/10.1084/jem.20091921] [PMID: 20156973]
[http://dx.doi.org/10.1038/nature11824] [PMID: 23376950]
[http://dx.doi.org/10.1002/ijc.25449] [PMID: 20473937]
[http://dx.doi.org/10.1016/j.cllc.2014.06.002] [PMID: 25044103]
[http://dx.doi.org/10.1080/21645515.2014.1004017] [PMID: 25585100]
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.4119]
[http://dx.doi.org/10.18632/oncotarget.19831] [PMID: 29137294]
[http://dx.doi.org/10.3390/vaccines2030515] [PMID: 26344743]
[http://dx.doi.org/10.1517/14712590902870386] [PMID: 19344285]
[http://dx.doi.org/10.4161/onci.23492] [PMID: 23734309]
[http://dx.doi.org/10.1586/erv.11.105] [PMID: 21919618]
[http://dx.doi.org/10.1080/2162402X.2016.1171446] [PMID: 27622022]
[http://dx.doi.org/10.7717/peerj.5056] [PMID: 30042874]
[http://dx.doi.org/10.1074/jbc.M411047200] [PMID: 15536075]
[http://dx.doi.org/10.1007/s00262-010-0872-7] [PMID: 20544195]
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0692] [PMID: 17975163]
[http://dx.doi.org/10.3748/wjg.v11.i12.1833] [PMID: 15793876]
[http://dx.doi.org/10.4049/jimmunol.176.10.6046] [PMID: 16670313]
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0371] [PMID: 19088033]
[http://dx.doi.org/10.4049/jimmunol.182.1.416] [PMID: 19109173]
[http://dx.doi.org/10.4049/jimmunol.0900364] [PMID: 19846865]
[http://dx.doi.org/10.1007/s12026-009-8120-y] [PMID: 19763891]
[http://dx.doi.org/10.1111/j.0022-202X.2004.23515.x] [PMID: 15654965]
[http://dx.doi.org/10.1016/j.peptides.2011.04.018] [PMID: 21539876]
[http://dx.doi.org/10.4161/hv.26568] [PMID: 24064957]
[http://dx.doi.org/10.5897/JCREO2015.0124]
[http://dx.doi.org/10.1016/j.vaccine.2008.11.014] [PMID: 19027812]
[http://dx.doi.org/10.1053/j.seminoncol.2012.02.007] [PMID: 22595050]
[PMID: 9108457]
[http://dx.doi.org/10.1186/1471-2407-8-360] [PMID: 19055839]
[http://dx.doi.org/10.1371/journal.pone.0028217] [PMID: 22140550]
[http://dx.doi.org/10.3747/co.2007.158] [PMID: 18080016]
[PMID: 19037836]
[http://dx.doi.org/10.1186/1471-2407-14-48] [PMID: 24475975]
[http://dx.doi.org/10.1038/nrc3258] [PMID: 22437871]
[http://dx.doi.org/10.1002/eji.201040630] [PMID: 20853498]
[http://dx.doi.org/10.1111/nyas.12125] [PMID: 23651191]
[http://dx.doi.org/10.18585/inabj.v8i1.189]
[http://dx.doi.org/10.1592/phco.31.8.813] [PMID: 21923608]
[http://dx.doi.org/10.1517/14712590903446921] [PMID: 19916735]
[http://dx.doi.org/10.2147/CE.S54712] [PMID: 25565923]
[http://dx.doi.org/10.1155/2010/174378] [PMID: 20368780]
[http://dx.doi.org/10.4161/21645515.2014.980686] [PMID: 25625927]
[http://dx.doi.org/10.1016/j.vaccine.2007.05.030] [PMID: 17698262]
[http://dx.doi.org/10.1086/515613] [PMID: 9652427]
[PMID: 11713825]
[http://dx.doi.org/10.1016/j.vaccine.2005.08.030] [PMID: 16154671]
[http://dx.doi.org/10.1038/gt.2014.67] [PMID: 25077772]
[http://dx.doi.org/10.1097/PPO.0b013e3182325e63] [PMID: 21952287]
[http://dx.doi.org/10.1016/B978-0-12-416603-5.00002-X]
[http://dx.doi.org/10.1093/jnci/84.14.1084] [PMID: 1619682]
[PMID: 9973217]
[http://dx.doi.org/10.1073/pnas.1408759111] [PMID: 25288727]
[http://dx.doi.org/10.1038/sj.cgt.7700733] [PMID: 15286681]
[http://dx.doi.org/10.2217/fvl-2017-0070]
[http://dx.doi.org/10.1038/ng0298-180] [PMID: 9462752]
[http://dx.doi.org/10.1016/j.ymgme.2003.08.016] [PMID: 14567964]
[http://dx.doi.org/10.2174/156652312800099599] [PMID: 22384806]
[PMID: 19956895]
[http://dx.doi.org/10.1016/j.addr.2009.04.012] [PMID: 19422865]
[PMID: 20677093]
[http://dx.doi.org/10.1007/s10529-009-0132-0] [PMID: 19784809]
[http://dx.doi.org/10.18632/oncotarget.16934] [PMID: 28445136]
[http://dx.doi.org/10.3390/biomedicines5010011] [PMID: 28536354]
[http://dx.doi.org/10.4161/rna.22269] [PMID: 23064118]
[http://dx.doi.org/10.1038/79519] [PMID: 10973321]
[http://dx.doi.org/10.1002/eji.200425656] [PMID: 15832293]
[http://dx.doi.org/10.1097/CJI.0b013e3181f7dbe8] [PMID: 21150709]
[http://dx.doi.org/10.1186/s40425-015-0058-0] [PMID: 25901285]
[http://dx.doi.org/10.1016/j.ejpb.2008.09.016] [PMID: 18948192]
[http://dx.doi.org/10.1016/j.coi.2011.03.007] [PMID: 21497074]
[http://dx.doi.org/10.1038/sj.gt.3302964] [PMID: 17476302]
[http://dx.doi.org/10.1172/JCI11405] [PMID: 11067858]
[PMID: 10779444]
[http://dx.doi.org/10.1182/blood.V98.9.2645] [PMID: 11675333]
[http://dx.doi.org/10.4161/hv.29553] [PMID: 25483661]
[http://dx.doi.org/10.1186/1471-2407-14-748] [PMID: 25288198]
[http://dx.doi.org/10.1038/mt.2010.289] [PMID: 21189474]
[http://dx.doi.org/10.2174/1389201019666180418095526] [PMID: 29667553]
[http://dx.doi.org/10.1056/NEJM198512053132327] [PMID: 3903508]
[http://dx.doi.org/10.1093/jnci/86.15.1159] [PMID: 8028037]
[http://dx.doi.org/10.1097/00002371-200205000-00007] [PMID: 12000866]
[http://dx.doi.org/10.18632/oncotarget.5463] [PMID: 26515587]
[http://dx.doi.org/10.1056/NEJM198812223192527] [PMID: 3264384]
[http://dx.doi.org/10.1126/science.aaa4967] [PMID: 25838374]
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0116] [PMID: 21498393]
[http://dx.doi.org/10.1097/CJI.0b013e31826e8f5f] [PMID: 22996367]
[http://dx.doi.org/10.1158/1078-0432.CCR-12-1177] [PMID: 23032743]
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0380] [PMID: 23690483]
[http://dx.doi.org/10.1200/JCO.2016.66.7220] [PMID: 27217459]
[http://dx.doi.org/10.1155/2018/9585614] [PMID: 29725606]
[http://dx.doi.org/10.1056/NEJMoa1609279] [PMID: 27959684]
[http://dx.doi.org/10.1158/2159-8290.CD-12-0548] [PMID: 23550147]
[http://dx.doi.org/10.1089/hum.2015.054] [PMID: 26230974]
[http://dx.doi.org/10.1016/j.canlet.2015.10.009] [PMID: 26477683]
[http://dx.doi.org/10.3389/fimmu.2013.00371] [PMID: 24273543]
[http://dx.doi.org/10.1016/j.apsb.2018.03.001] [PMID: 30109179]
[http://dx.doi.org/10.1038/nrc3239] [PMID: 22437870]
[http://dx.doi.org/10.1200/JCO.2014.59.4358] [PMID: 25605845]
[http://dx.doi.org/10.1016/j.ccell.2015.03.001] [PMID: 25858804]
[http://dx.doi.org/10.1126/science.aar4060] [PMID: 29567705]
[http://dx.doi.org/10.1172/jci.insight.121077] [PMID: 29997294]
[http://dx.doi.org/10.20517/2394-4722.2017.41]
[http://dx.doi.org/10.3390/cancers3043856] [PMID: 24213115]
[http://dx.doi.org/10.1586/14737140.2014.928596] [PMID: 24928447]
[http://dx.doi.org/10.1158/2326-6066.CIR-17-0655] [PMID: 29764837]
[http://dx.doi.org/10.21037/tlcr.2018.09.04] [PMID: 30393613]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-3726] [PMID: 19435913]
[http://dx.doi.org/10.1002/ijc.24597] [PMID: 19621448]
[http://dx.doi.org/10.1038/nm.2883] [PMID: 22842478]
[http://dx.doi.org/10.2217/imt.09.4] [PMID: 20352015]
[http://dx.doi.org/10.7150/jca.1.230] [PMID: 21151581]
[http://dx.doi.org/10.1089/hum.1998.9.6-835] [PMID: 9581906]
[http://dx.doi.org/10.1200/JCO.2005.05.5335] [PMID: 16966690]
[http://dx.doi.org/10.1126/science.aar7112] [PMID: 29567706]
[http://dx.doi.org/10.1186/1479-0556-4-4] [PMID: 16732888]
[http://dx.doi.org/10.1002/jgm.2605] [PMID: 22262664]
[http://dx.doi.org/10.1002/eji.1830230749] [PMID: 8325342]
[http://dx.doi.org/10.1182/blood-2011-10-384388] [PMID: 22160384]
[http://dx.doi.org/10.1016/j.hoc.2013.01.003] [PMID: 23561470]
[http://dx.doi.org/10.1038/mto.2016.11] [PMID: 27626062]
[http://dx.doi.org/10.1186/s40164-017-0070-9] [PMID: 28413717]
[http://dx.doi.org/10.1177/1010428317692226] [PMID: 28218037]
[http://dx.doi.org/10.1078/1438-4221-00302] [PMID: 15149034]
[http://dx.doi.org/10.1385/MB:18:3:251] [PMID: 11503519]
[http://dx.doi.org/10.1016/j.ejca.2017.01.035] [PMID: 28623775]
[http://dx.doi.org/10.1093/pcmedi/pby011] [PMID: 30687562]
[http://dx.doi.org/10.1158/1541-7786.MCR-16-0427] [PMID: 28356330]