Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application.

0.47 MB·English

by  Furqan, Muhammad

Furqanetal.BiomarkerResearch2013,1:5
http://www.biomarkerres.org/content/1/1/5
REVIEW Open Access
Dysregulation of JAK-STAT pathway in
hematological malignancies and JAK inhibitors for
clinical application
Muhammad Furqan1, Nikhil Mukhi1, Byung Lee2 and Delong Liu1*
Abstract
JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical rolein
transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune
regulation, fertility,lactation, growthand embryogenesis.JAK family contains four cytoplasmic tyrosine kinases,
JAK1-3 and Tyk2. SevenSTAT proteins have been identified inhuman cells, STAT1-6,including STAT5a and STAT5b.
Negative regulators of JAK–STAT pathways includetyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of
activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins,and cytokine-inducible SH2-containing
protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological
malignancies. JAK inhibitors are among thefirst successful agents reaching clinical application. Ruxolitinib (Jakafi), a
non-selective inhibitor of JAK1 & 2, has been approvedby FDA for patients with intermediate to high risk primary
or secondary myelofibrosis.This review will also summarize early data onselective JAK inhibitors, including
SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544,XL019, BMS-911543, NS-018,
and AZD1480.
Introduction activity. Subsequently activated JAKs phosphorylate cy-
JAK-STAT (Janus associated kinase-signal transducer toplasmic domain of the receptor [9]. Activated JAK-
and activator of transcription) pathway is one of the cri- cytokine receptor complex recruits and phosphorylates
tical intracellular signaling cascades in transduction of specific cytoplasmic transcription factors called STAT
extracellularsignalstothenucleustocontrolgeneexpres- proteins [10]. Seven STAT proteins have been identified
sion. A variety of cytokines and growth factors complete inhuman cells, STAT1-6,including STAT5aand STAT5b
their physiological tasks through JAK-STAT pathway, in- [7]. Phosphorylation of specific STAT proteins results in
cluding hematopoiesis, immune-regulation, fertility, lacta- their dimerization and subsequent translocation into the
tion,growthandembryogenesis[1-6]. nucleus to interact with various regulatory elements for
JAK family contains four cytoplasmic tyrosine kinases, geneexpression(Figure1)[11,12].
JAK1-3 and Tyk2 [7]. These kinases bind to the juxta-
membraneregionofcytokinereceptors[8].Eachmolecule
Regulation of JAK-STAT pathway
contains seven JAK homology domains (JH1-7). The car-
Three major mechanisms have been implicated to ne-
boxyl JH1 domain contains the catalytic activity, whereas
gatively regulate the JAK-STAT pathway [11]. Figure 1
N-terminal JH7 domain is responsible for receptor bind-
depicts the positive and negative regulation of the JAK-
ing.JH2domainhassignificanthomologytoJH1butlacks
STATpathway.
enzymatic activity and therefore is a pseudo-kinase do-
main. Binding of a ligand to its receptor results in recep-
tor dimerization, leading to activation of the JAK kinase Tyrosinephosphatases
Src homology-2 (SH2) containing tyrosine phosphatase
*Correspondence:[email protected] andCD45tyrosinephosphataseplayamajorroleinmodu-
1DepartmentofMedicine,NewYorkMedicalCollegeandWestchester
lating JAK-STAT pathway. SH2 containing tyrosine phos-
MedicalCenter,Valhalla,NY10595,USA
Fulllistofauthorinformationisavailableattheendofthearticle phatases include SHP1 and SHP2 (shatterproof 1 & 2).
©2013Furqanetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
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Figure1SignalingcascadeofJAK-STATpathway.Bindingoftheligandtocytokinereceptorinducesreceptordimerizationandactivationof
receptorassociatedJAKkinase,whichinturnphosphorylatesSTATproteins.Afterformingahomodimer,STATproteinstranslocatetothenucleus
tocontrolgeneexpression.NegativeregulationoftheJAK-STATpathwayisprovidedbyphospho-tyrosinephosphatases(PTP),memberforSOCS
familyproteinsandPIASproteins(showninred).
Their SH2 domains allow attachment to the phospho- SH2-containing protein (CIS). SOCS proteins are cyto-
tyrosine residues present on activated receptors, JAKs or kine-induced negative feedback-loop regulators of JAK-
STAT proteins, leading to dephosphorylation of the sub- STATsignaling. Each member protein in this family has
strates. SHP1 is mainly expressed in hematopoietic cells, a central SH2 domain, variable amino-terminal domain
epithelial and smooth muscle cells whereas SHP2 is ubi- and a carboxy-terminal of 40 amino acids module known
quitous. The expression of SHP1 gene was found to be as SOCS box. The central SH2 domain directs the target
silencedbypromoterhypermethylationinvarioushemato- binding of each CIS/SOCS protein [18]. Three mecha-
logical malignancies [10]. CD45 transmembrane tyrosine nisms have been proposed by which a SOCS protein
phosphatase is the second type of tyrosine phosphatase providesnegativemodulation.First,SOCSbindsthephos-
that negatively regulates JAK-STAT pathway. CD45, the pho-tyrosine residues on the receptors and physically
leukocyte common antigen, is expressed in hematopoietic blocks the STATs from binding to its receptors. Second,
cells. It has two phosphatase domains in its intracellular SOCS proteins can bind directly to its specific JAKs or to
region,thoughonlyoneisactive.MicedeficientforCD45 the receptors and inhibit the corresponding JAK kinase
showhyper-activationofJAK1andJAK3[10]. activity. Third, SOCS associate with the elongin BC com-
plex and cullin 2, accelerating the ubiquination of JAKs
ProteininhibitorsofactivatedSTATs(PIAS) andpresumablythereceptors[19].
PIASfamilyconsists of PIAS1, PIAS3, PIASx and PIASy. EndosomaldegradationofJAK/receptorcomplexthrough
Biochemicalassays haveshown thatPIAS3and PIASxin- receptor mediated endocytosis appears to be another me-
teract with STAT3 and STAT4 respectively, while PIAS1 chanisminvolvedintheregulationofthepathway.STAT5ß
and PIASy with STAT1 [13,14]. PIAS1 and PIAS3 exert dimerizes with the full-length, wild-type protein, STAT5α,
negative regulation by blocking the DNA binding of upon activation. This leads to negative regulation of the
STAT1 and STAT3, respectively [15,16]. On the other JAK-STATsignaling cascade in addition to the major me-
hand, PIASx and PIASy repress the transcriptional ac- chanismsdescribedabove[20].
tivity of STAT1 and STAT4 by recruiting co-repressor
molecules such as histone deacetylases [17].
JAK-STAT pathway and hematological
Suppressorsofcytokinesignaling(SOCS)proteins malignancies
The suppressor of cytokine signaling (SOCS) family is Dysregulation in JAK-STAT pathway have been described
composed of SOCS-1 to SOCS-7 and cytokine-inducible in a variety of hematological malignancies, especially in
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myeloiddisorders.Theseeventsmayplaykeyrolesinini- Lymphomaandlymphoidleukemia
tiationandprogressionofrespectivediseases. T-celllymphomaandleukemia
JAK1 gene plays a unique role in lymphohematopoiesis.
Flex et al., showed several acquired JAK1 missense
Myeloproliferative Neoplasms (MPN) mutations in adult lymphoblastic leukemia, especially in
PhnegativeMPNs T-cell precursor type where it accounted for 18% of the
Short interfering RNA and JAK2 inhibitor (AG490) have cases. It was associated with advanced age and poor
beenusedtostudytheactivityofJAK2.JAK2wasshown prognosis[34-36].
to be central to the erythropoietin-independent eryth- Translocation between short-arm of chromosome 9
roid proliferation in polycythemia vera (PV). A common (harboring JAK2 gene) and 12, t(9;12)(p24;p13) results
mutation (V617F) in the JH2 pseudo-kinase domain of in the formation of a fusion protein, TEL-JAK2. This
JAK2 wasshownin80% ofthe patients [21].Thisresults results in constitutive JAK2 activation. It was found in a
in constitutive activation of STAT5 and a malignant case of childhood T-cell acute lymphoblastic leukemia
phenotype [22]. Other investigators confirmed the fact [37]andinacasewithpre-B-cellALL[33].
and showedthat30-50% ofpatients withessential throm-
bocythemia (ET) and primary myelofibrosis (PMF) also AdultT-cellLeukemia(HTLV-1positive)
harborthesamemutation[23-25]. HumanT-celllymphotropic virus-1encodedTaxprotein
AllelicburdenofJAK2V617Fwasfound toplayanim- suppresses apoptosis through constitutive activation of
portant role in determining a distinct clinico-pathologic the NFκB pathway. This is sufficient for immortalization
phenotype from the same mutation [22,26]. It is sug- of CD4+ lymphocytes. HTLV-1 infected T-cells over-ex-
gested by the fact that homozygous JAK2V617F mu- press IL-2, IL-15 as well as IL-2 and IL-15 receptors by
tation is 30% in PV compared to 2-4% in ET [22,26]. Tax-induced NFκB activation. These in turn activate
Transgenic mouse models and clinical cases support JAK3-STAT5 pathway leading to lymphocyte prolifera-
the gene-dosage model for MPN pathogenesis. It was tion andadultT-celllymphoma/leukemia[38].
observed that high allele burden leads to PV pheno-
type, whereas reduction in allelic burden leads to ET T-cellLargeGranularLymphocyticLeukemia,Anaplastic
[22,27-29]. LargecellLymphoma,AngioimmunoblasticLymphomaand
In patients with PV who are negative for JAK2V617F, SezarySyndrome
Scott et al., used a candidate gene approach to search Dysregulation of STAT proteins also contributes to the
for alleles that can activate JAK signaling. Their work pathogenesis of various types of lymphoid malignancies.
demonstratedatleast8distinctmutations involvingresi- Schade et al., reported increase activity of STAT3 in T-
dues538to543inexon12regionofJAK2[29]. cell large granular lymphocytic leukemia [39]. Constitu-
Irrespective of JAK2V617F status, patients with PV tive activation of STAT3 & 5 was also found to be an
exhibits high STAT3 and 5 activities, patients with ET important event in the pathogenesis of anaplastic large
have high STAT3 activity, whereas patients with PMF cell lymphoma, T-cell angioimmunoblastic lymphoma
showed low activities of both STAT3 and 5. It is evident andSezarysyndrome[40,41].
that preferential activation of JAK2–STAT5 or JAK2–
STAT3 signaling determines PV, ET and PMF pheno- B-Cell lymphoma and leukemia
type. However patients with JAK2V617F-negative ET or Acutelymphoblasticleukemia
PMF may harbor mutations in other genes in JAK– Kearney et al., performed sequencing of exon 14 of
STATpathway[30]. JAK2 gene in patients with Down syndrome associated
ALL.Anacquired somaticpointmutationinvovling resi-
due R683 was found in 28% of cases [42]. A different
AtypicalMPNs mutation in JAK2 gene in a patient with Down syn-
Rare JAK2 gene rearrangement can result in atypical drome associated precursor B-cell lymphoblastic
form of chronic myeloid leukemia (aCML). These gene leukemia was reported by Malinge et al., This mutation
rearrangements include PCM1-JAK2, TEL-JAK2 and was in-frame deletion of five-amino acid residues from
BCR-JAK2 [31-33].Rarely,JAK2V617F mutationcanpre- position 682 to 686, named as IREED mutation, in the
sent phenotypically as chronic myelomonocytic leuke- pseudokinase domain of JAK2. This IREED mutant
mia /aCML. remains constitutively active and induces cytokine in-
PCM1-JAK2 gene rearrangement was discovered in dependence in Ba/F3 cells [43].
the translocation, t(8;9)(p22;p24). It is reported in few Another JAK2 mutation involves fusion with SSBP2 in
cases with atypical CML, chronic eosinophilic leukemia, t(5;9)(q14.1;p24.1) translocation. It was detected in a pa-
AML(M2, M6), preB-ALL andT-celllymphoma. tient withpre B-cell ALL[44].
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Chroniclymphocyticleukemia sideroblast associated with marked thrombocytosis
Constitutive activation of STAT1 & 3 was noticed in (RARS-t). These patients have features of both MDS and
transformed B-cells in patients with chronic lymphocytic MPN.Itwasrecentlyshownthat6outof9(67%)patients
leukemia (CLL). Activated STAT1 & 3 proteins in ma- withRARS-thaveJAK2V617Fmutation[54].
lignant B-cells were phosporylated at serine instead of
tyrosineresidue.Itremaineduncertainwhetheractivated Multiple myeloma
STAT involved directly in the pathophysiology of this Constitutive expression of STAT3 has been seen fre-
diseaseorrepresentedapureepi-phenomenon [45]. quentlyinpatientswithmultiplemyelomaandlymphoma
[55]. However, overexpression of anti-apoptotic proteins
PrimarymediastinalB-celllymphoma ofBcl-2,Bcl-XLandMcl-1maynotrelyonSTAT3activa-
A bi-allelic mutation in SOCS-1 has been reported in tion.Theroleofthispathwayinpathogenesisofmyeloma
primary mediastinal B-cell lymphoma. This results in remainstobedetermined[56].
delayed turnover of phosphorylated JAK2 and increased
activity of STAT5, which may explain the uncontrolled
Novel inhibitors of JAK-STAT pathway
growth ofmalignantcells [46].
The specific and profound involvement of JAK-STAT
pathway in various hematological malignancies, espe-
Hodgkinlymphoma
cially Bcr-Abl negative MPNs, makes them ideal targets
Gene rearrangement by translocation involving JAK2,
for pharmacological intervention [57]. Several strategies
t(4;9)(q21;p24), has been reported in 2 cases of classic
have been proposed to inhibit or modulate this pathway
Hodgkin lymphoma by a group from Belgium [47]. This
[58,59]. JAK inhibitors are among the first successful
gene re-arrangement creates a novel fusion product,
agentsreachingclinicalapplication[60,61].
SEC31A-JAK2. This oncogenic SEC31A-JAK2 has consti-
tutivelyactivetyrosinekinaseactivity.MutationsofSOCS-
JAK inhibitors
1havealsobeenidentifiedinHodgkinlymphoma[48].
There are at least 10 different JAK inhibitors undergoing
various phases of clinical trials (Table 1). Ruxolitinib
Myeloid leukemia
(Jakafi manufactured by Incyte, Inc) has been approved
Acutemyeloidleukemia
by FDA for patients with intermediate- to high- risk pri-
Increased activity of STAT3 has been reported in 20-50%
maryorsecondarymyelofibrosis.
of AML patients while STAT5 and STAT1 activation
is uncommon [49,50]. The pathologic value of activated
STAT3inAMLisunclear.Itwasalsofoundinacutepro- Ruxolitinib
myelocytic leukemia (APL). An interstitial deletion within Ruxolitinib (INCB018424) is a non-selective JAK1 &
chromosome 17 has been described to result in STAT5b- 2 inhibitor. Multiple phase I/II studies in various he-
RARα fusion protein. This was implied to serve as a key matological malignancies are underway. Among these,
pathogenic event in a patient with APL [51]. Transfor- results are most mature for PMF and post –ET /PV
mation from severe congenital neutropenia due to trun- myelofibrosis.
catedG-CSFreceptortoAML alsoinvolvesdysregulation
of STAT proteins. Truncated G-CSF receptor lacks a PhaseI/IIstudies
crucial binding site for SOCS-3, thus relieving inhibition A total of 153 patients with myelofibrosis were recrui-
of STAT5, but not of STAT3. This favors myeloid pro- ted in a phase I/II study. Dose limiting toxicity was
liferation over differentiation. These truncated receptors thrombocytopenia with maximum tolerated dose of
are also resistant to down modulation through ubiqui- 25 mg twice daily. Effect on JAK2V617F allele burden
nation [52]. or bone marrow fibrosis was insignificant [62]. After a
Rare point mutations, one in JAK2 (T875N) and three longer follow up, it was described that abrupt discon-
in JAK3 (A572V, V722I, P132T), have been described in tinuation can lead to serious adverse events like acute
patients withacutemegakaryocyticluekemia[52].PCM1- relapse of constitutional symptoms, rapid and painful
JAK2 gene rearrangement mentioned above was found in enlargement of spleen and shock. By the time of last re-
M2andM6AML[36]. port on the follow up of these patients 35% of patient
diedand10%transformedtoleukemia[63,64].
Myelodysplastic syndrome (MDS) Eghtedar et al., reported a phase I/II study of ruxoli-
Perturbation inJAK-STATpathway israreinMDS.Only tinib in patients with relapsed /refractory AML. This
4.2%patientswithMDSwerefoundtoharborJAK2V617F study has shown 7% complete remission rate. It was no-
mutation in a large screening series [53]. Of interest is a ticed that patients who achieved complete remission
disease entity called refractory anemia with ringed were those withpost-MPNAML[65].
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Table1JAKinhibitorsinclinicaltrials
Drugs JAK Non-JAKTarget Trials:status Diseaseunderstudy
Target
(Ref)
INCB018424(Ruxolitinib) JAK1&2 NR III:Reported PMF,PostET/PVMF,
III:recruiting PV(intolerantorresistanttoHU)
FDAApproved II:Recruiting PV,ET
[62-67] I/II:Recruiting AML/ALL(Relapse/Refractory)
II:Completed MM(Relapse/Refractory)
II:Recruiting DLBCL/T-CellLymphoma
II:Active AdvancedHemMalignancies
SAR302503 JAK2 FLT3 III:Recruiting PMF
(TG101348) RET II:Recruiting PV,ET
[70]
CEP-701 JAK2 FLT3 II:Completed ET,PV
(Lestaurtinib) JAK3 VEGFR2 II:Completed AML(FLT3)
[71,72] TRKA III:Recruiting ALL(children)
RET II:Recruiting PMF
CYT387 JAK1,2 PKD3,PRKD1,CDK2,ROCK2,JNK1 II:Recruiting PMF,PostPV/ETMF
[77,78] Tyk2
SB1518 JAK2 FLT3 II:Completed PMF
[83,84] II:Completed AdvMyeloidmalignancies
II:Completed AdvLymphoidmalignancies
II:Recruiting MDS
LY2784544 JAK2V617F NA I/II:Recruiting PMF,ET,PV
[85]
XL019 JAK2 NA I:Terminated PMF
[86]
AZD1480 JAK1-3 FGFR1,FLT4,ARK5,ALK4,Aurora-A I/II:Active PMF,PostET/PVMF
[91]
BMS-911543 JAK2 Noinformation I/II:active PMF
[90]
NS018 JAK2 SrcKinases I/II:active PMF,PostET/PVMF
[89]
Ref,references;NR,nonereported;HU,hydroxyurea;AML,acutemyeloidleukemia;ALL,acutelymphoidleukemia;MM,multipleMyeloma;DLBCL,diffuselarge
B-celllymphoma.
PhaseIIIstudies of these trials and major outcomes are summarized in
Ruxolitinib has undergone 2 separate randomized con- Table2.
trolled trials, referred to as the COntrolled MyeloFibrosis These trials support the palliative role of ruxolitinib
study with ORal JAK inhibitor Treatment (COMFORT) I which significantly reduced spleen volume and consti-
& II (Table 2) [66,67]. Patients were randomized between tutional symptoms. The responses were not specific for
ruxolitinib vs placebo (COMFORT I) or best available JAK2 mutation.
therapy (COMFORT II). Patients with PMF or post –ET
/PV myelofibrosis must have high or intermediate inter- SAR302503(TG101348)
national prognostic scores, palpable spleen ≥5 cm below SAR302503 is a selective JAK2 inhibitor with activity
the left costal margin, and platelet count equal or greater on both wild type and mutant JAK2 [68,69]. Fifty nine
than 100 × 109 /L. Patients were recruited irrespective patients were enrolled in a multi-center phase I/II trial
of JAK2 gene mutation status. Differences in the design with high-or- intermediate-risk primary or post-PV/ET
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Table2COMFORT-I&IItrialsonruxolitinib
Methodology COMFORT-I COMFORT-II
Design 1:1randomization,vs.placebo 2:1randomization,vs.bestavailabletherapy
Numberofpatients 155(ruxolitib)vs.154(placebo) 146(ruxolitinib)vs.73(BAT)
Doseofruxolitinib 15-20mgtwicedailybasedonplateletcount 15-20mgtwicedailybasedonplateletcount
Primaryendpoint reductioninspleensize>35%at24week reductionofspleensize>35%at48week
Results
35%reductioninspleensize 42%vs.0.7%at24week 28%vs.0%at48week
Durationofspleenresponse* 67%patientmaintainedthespleenresponsefor48weeks 80%maintainedtheresponseat12monthfollowup
MajorAdverseevents: Anemia(45%),Thrombocytopenia(13%),headache,pyrexia Anemia,Diarrhea,Arthralgia,fatigue,abdominalpain
DiscontinuationRate 11%vs.10.6% 8%vs.5%
BAT,bestavailabletherapy;*,secondaryend-points;QOL,qualityoflife;ns,nonsignificant.
myelofibrosis. Patients with platelet count equal or grea- CYT387 has significantly less activity against other ki-
ter than 50 x 109 /L were eligible. Reversible increase in nases,includingJAK3 (IC50=0.16μM).
serum amylase was the dose limiting toxicity. Serious One hundred sixty three patients with high- or in-
adverse events included mainly myelosuppression and termediate- risk myelofibrosis were enrolled in a phase
gastrointestinal toxicity. A spleen response of 47% was I/II trial of CYT387. The median duration of treatment
seenafteroneyearoftreatment.JAK2V617Falleleburden was 6.6 months. Dose limiting toxicities included hyper-
was significantly decreased at 6 months in mutation- lipasemia and headaches. Maximum tolerated dose was
positive patients (n = 51; P = .04). The response was 300 mg/day. The response rates for reduction of spleen
higher in patients with allele burden greater than 20% size, anemia, and constitutional symptom were 45%,
(n = 23; P < .01) [70]. A multinational, randomized, pla- 50%, and more than 50%, respectively. It is interesting to
cebo controlled phase III trial has been launched recently note that responses were also seen in patients who had
forpatientswithhighriskmyelofibrosis. previously failed ruxolitinib or SAR302503. Surprisingly,
58%oftransfusion-dependentpatientsbecametransfusion-
independent. Transient light headedness and hypotension
Lestaurtinib(CEP701)
werethecommonadverseevents.Treatment-relatedsevere
Lestaurtinib is an orally available indolocarbazole deriva-
anemia was infrequent (< 1%). This property separates it
tive. It was originally identified as an inhibitor of the
fromruxolitinibandSAR302503[77,78].
neurotropin receptor TrkA. It was found to also inhibit
FLT3, JAK2 and JAK3. Due to its strong activity against
FLT3, it is under investigation in patients with acute
SB1518(pacritinib)
leukemia. A phase I/II study of lestaurtinib was done
Pacritinib is another orally bioavailable ATP-competi-
in 22 patients with JAK2-mutated myelofibrosis. The
tive small molecule inhibitor of JAK2 and the mutant
patients received 80 mg twice-daily. The response rate
JAK2V617F [79-82]. It inhibitis JAK-STAT signaling
was 27%. The median duration of response was mo-
pathway through caspase-dependent apoptosis. In a
re than 14 months. However, bone marrow fibrosis
phase I/II trial, 34 patients with primary or post PV/ET
or JAK2V617F allele burden was not significantly al-
myelofibrosis were enrolled. The median time on study
tered [71].
was 8.2 months. Patients with low blood counts were
In another phase 2 study, lestaurtinib was given to 39
not excluded. Most common adverse events were diar-
high-risk patients with JAK2V617F-positive PV (n=27)
rhea, nausea and vomiting. The primary end point was
or ET (n=12). After 18 weeks of treatment, a significant
spleen response, which was 32%. The median duration
decrease in spleen size was reported in 83% of the
of spleen response has not been reached at the recent
patients. Six patient developed thrombosis. The increase
update [83].
in the thrombotic events remains a concern for this
In another phase I trial, 30 patients with relapsed/
agent[72].
refractory lymphoma were enrolled. The dose was es-
calated from 200–600 mg/day. Severe adverse events in-
CYT387 cluded cytopenia, internal hemorrhage, various infections
CYT387 is an ATP-competitive small molecule JAK1/ and abdominal distention. No patient achieved complete
JAK2 inhibitor [73-76]. It has an IC50 of 11 and 18 nM remission. Three patients had partial remission and 13
for JAK1 and JAK2, respectively. Unlike lestaurtinib, patientshadstabledisease[84].PhaseIItrialisongoing.
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LY2784544 approaches are still at early stage and only supported by
LY2784544 is a selective mutant JAK2 kinase inhibitor pre-clinical data [13,100-107]. Further advancement in
with an IC50 of 68 nM. This molecule selectively inhib- understanding the molecular events and refining the tar-
ited the JAK2 V617F-STAT5signaling at aconcentration gets can potentially lead to further clinical benefit. Si-
thatwas41-foldlowerthanthatneededforthewildtype multaneousinterventionatmultiplelevelsofthesignaling
(WT) JAK2 signaling (IC50 = 55 nM for V617F vs. 2260 cascadeby combiningdifferent targeting agents mayoffer
nM for WT ) [60]. A phase I/II trial recruited 19 pa- additionaladvantagesandisworthwhilestudying.
tients with Ph negative MPN. Maximum tolerated dose
was 120 mg/day. Spleen response was 22% for patients Competinginterest
Theauthorshavenorelevantconflictsofinterest.
with MF. JAK2V617F allele burden was not significantly
decreased. Main adverse events included diarrhea, nau-
Authors’contributions
sea,anemia andelectrolyte imbalance[85]. Allauthorshavecontributedtodatapreparation,draftingandrevisingthe
manuscripts.Allauthorshavereadandapprovedthefinalmanuscript.
XL019
XL019 represents another oral selective JAK2 inhibitor Acknowledgment
ThisstudywaspartlysupportedbyNewYorkMedicalCollegeBlood
(IC50= 2nM for JAK2, 130 nM for JAK1, 250 nM for
DiseasesFund.
JAK3, 340 nM for TYK2) [86,87]. A phase I study
recruited 21 patients with myelofibrosis. 16 patients had Authordetails
1DepartmentofMedicine,NewYorkMedicalCollegeandWestchester
JAK2V617F, one had MPL W515F. Dose ranged from 25 MedicalCenter,Valhalla,NY10595,USA.2CaliforniaCancerCenter,7257N.
to 300 mg. Surprisingly, there was no hematological ad- FresnoSt.,Fresno,CA93720-2950,USA.
verse events. Improvement in clinical outcome observed
Received:12September2012Accepted:14September2012
in all patients with JAK2V617F or MPL activating muta-
Published:16January2013
tions [86]. Despite these results, further development of
clinical trials using XL019 was aborted out of the con- References
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