Abstract
With 1.67 million new cases and 522,000 deaths in the year 2012, breast cancer is the most common type of diagnosed malignancy and the second leading cause of cancer death in women around the world. Despite the success of screening programs and the development of adjuvant therapies, a significant percentage of breast cancer patients will suffer a metastatic disease that, to this day, remains incurable and justifies the research of new therapies to improve their life expectancy. Among the new therapies that have been developed in recent years, the emergence of targeted therapies has been a milestone in the fight against cancer. Over the past decade, many studies have shown a causal role of protein kinase dysregulations or mutations in different human diseases, including cancer. Along these lines, cancer research has demonstrated a key role of many protein kinases during human tumorigenesis and cancer progression, turning these molecules into valid candidates for new targeted therapies. The subsequent discovery and introduction in 2001 of the kinase inhibitor imatinib, as a targeted treatment for chronic myelogenous leukemia, revolutionized cancer genetic pathways research, and lead to the development of multiple small-molecule kinase inhibitors against various malignancies, including breast cancer. In this review, we analyze studies published to date about novel small-molecule kinase inhibitors and evaluate if they would be useful to develop new treatment strategies for breast cancer patients.
Highlights
Nowadays, most breast cancers are diagnosed early enough to be successfully treated with surgery, chemotherapy, radiotherapy, or a combination thereof, a significant percentage of patients will not respond to these treatments and end up with metastatic disease to bone, lung, liver, brain [2], or other body organs, causing a patient’s death [3], which justifies the search of new therapeutic strategies
Mitotic kinases, including Cyclin-Dependent Kinases (CDK), Aurora (AURK), Polo-like (PLK) and NIMA (Never In Mitosis)-related kinase families play an important role as regulators of cell division and cytokinesis and their dysregulation has been related to tumorigenesis [90,91] (Table 8)
Sphingosine kinase (SK, SphK) isozymes are a class of G protein-coupled receptor kinases (GRK) that catalyze the phosphorylation of sphingosine into sphingosine-1-phosphate (S1P)
Summary
Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer death among women worldwide [1]. HER2r.e21s-.E1p.noHnrisEcehR[e22d-0E,2n3r,i2c5h]e.d eafdobsaauxnnvrimfetbdtefeiaetrbinyHserlHHToytespxhE,dincuEpeveRatymRtre[inifdeHobstte4a2fd2eHobslg2rrauxatsycavrati6ux.aavr(hirEmifse1etnbEmpief]EeotssafbeeistsaRf..reetrattRop1ilnrsetrntsyisuuelenyrc4yHHTbsute.lnrr,y4HHTtsepxpuyotazzseopxBHhdit,nhEupc(i,enuurvnizinhEupcv(e-veEidsaeteEEmRru4tademmestimRr[eitenirle[esi)a2tnalRirwde2mgada2baly2a,gsiarcaba6tpyascptth26tpsBmnHiephibbuiesBa]aniespoiid-r]strspo.-idstootnbrtE.tlo-Enoasr4htlehunyeisr4(npcuydeo,ntlv)ncRlHao,pe)doea(,tpytdvotar,esvHtorg2oiirinhnaiieiriHnhnedsnliaeecHedsrksdryeedisr(dedispdleohidetEctdEnlwesrcasrtEwhraiwayeaeariocrpottRatawmpttRtaieicdpmpeuhmbeinpnneudwhrt2ntdrd2ptoBteehoadifshdoteeoaitaidevnorlpilttn2tvr(rlpillttv(aiileEyaatafrba/eti)eEntyatgtopatiedcortgnuopriilonnor)rearlctnekytybseresktHyybsioehtdltinoeosBccdtwtilonshBucwwafahschysErownoaf2oyrioe)2ctiroieaennciwR/teanpirsnitw/t[nilrnhttmrbilsnnbhr1slh2ttisvealnhHtetevnierH1idet-biraicppodaniufiagibddta,ufaEmbeeaitt1tnurEpneatdm)unitou.nres)pcioRo9tesctRsritsplcddittsie]tcvveditTaocio2odoserc.o2oodossrsmeeto-ixtsfnrryi-irnrebrdoyiadnnbigidaapnttsabpme[ssrroane2e[crrrt1ntmeidiraeat1miendieetahgv1aiebrovcnph1.i(goalcpt.ieneeg,mterlHneeTo,dm1peenuenTmn1eptpuamnop9fprohlrpdl9aEolrpytlau]oobbtrgitbea]sooowbg.bRnhooot.fxtletrert2bfxrreeerocregr2elaieirtt0ielritmottscha)apmofs2chcEha–ai2-cokmenisepoegaceena3seergfrsatrlkt(Hfnuatnnbrt0let(alnHtelcwHtsttcBat%rettcwttEahhfplhaihiihepllhEayoclcoiEtiyeRnwmrerieietnrnehRrohtonnRhtrco21hrcgEaa2feeaep2legEea02lieiHiyrm0dpr)ir(sbHafxpn–r)rgf-eEb–esp-etbrteepE3iebexeE3irBrmGeusatrnBt0eusaRatrantl0haRhattne%rarFtttcha%frm1isettheaiihma1incoteiRihmctowcsccowd(eleraeho(ent/EcelheontEwmiahmgaufepaatmahlnEGfehyrGylgudilnyriabudiugabngarbustFrbngrmsctFbrrhmrrloeerimRremeaeyaRtmBettelssatathlrtaroead/nhniasea/-hnafnsEnseatafnE1iooeseatnmudioetvirdmecs[t)isrmrdziabrz1,moeetacbizmetwkctigypmen1BlamHgyapenByadHliodg,rgan-ainidgr1gapn-aon1Etrartopr1cEr2athrcseimes)iyRiemems)te]syr,neRitseo,oi.rsonotenoh3HorsnnHsh2osfotfsleitAtanorueiti-vcn(isEnucv[cesfEvHpsfEo[ems1keeoaoRemc1wkeeRoclwrc1riEcenlHclH13iolbHnlasa3,olipHnlocR,b1iotrioBnat1Ep(EtreatnthEp(2sieE2nhEsn2ioc-EoRrrsRa]evRr.e3ra]e,oRrate.nhroln2t.2bhe)hslr2rllbAhA2,,arl.iaeABari-iaBfei-vspfeslnvses-pnctse-iec3orthce3sortcHeia)Hasitpa)obas,pbbati,nbtEiuotnaitEenotaitooiecnRodoigcevnRdceevnrenrdnhy2eesrdny2e,sr, dtreavsetluozpummeanbt i(sHaerecceuprtirne)ntthparot bblienmdsthtaot hanasdmboloticvkastetdhetheexstreaacreclhluolfaraldteormnaatinveotfheHraEpRi2e.s Atalrtgheotuinggh tthriasstuyzrousminaebkhiansasderarmecaetpictoalrl.yInimthpirsovreegdatrhde, tohuetcuosme eofosrmpaaltlieknintsasweitihnhthibiistotyrps elikofeclanpcaetirn, irbe/sTisytkanebce, ndeervaetilnoipbm[e2n7t],isgaefriteicnuibrre[1n1t]p, roorblaefmatitnhiabt [h2a8s] mhaovtievastheodwtnhepsreeacrlcinhicoaflaaltnedrncaltinviecathl eervaipdieensctearignettihneg ttrheiastmtyernotsionfeHkEinRa2s-eenrericcehpetdort.uImn othrsis(Treagbalerd2,).the use of small kinase inhibitors like lapatinib/Tykeb, trastuzumab has dramatically improved the outcome for patients with this type of cancer, resistance development is a recurrent problem that has motivated the search of alternative therapies targeting this tyrosine kinase receptor. In this regard, the use of small kinase inhibitors like lapatinib/Tykeb, neratinib [27], gefitinib [11], or afatinib [28] have shown preclinical and clinical evidence in the treatment of HER2-enriched tumors (Table 2). Many protein kinase-encoding genes appear to be altered in ER-positive breast tumors [41,49], which has opened the possibility of developing treatment strategies for these tumors that are based on the targeted inhibition of altered kinases
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