polo-like kinase 1 inhibitors and their potential role in...

Review

Polo-like Kinase 1 Inhibitors and Their Potential Rolein Anticancer Therapy, with a Focus on NSCLC

Ren�e H. Medema1, Chia-Chi Lin2, and James Chih-Hsin Yang2,3

AbstractCytotoxic platinum-doublet chemotherapy that includes antimitotic agents is a current standard of care

in advanced non–small cell lung cancer (NSCLC). Microtubule-targeting antimitotics, taxanes, and Vinca

alkaloids are effective anticancer therapeutics that affect both dividing and nondividing cells. A new

generation of antimitotic agents that target regulatory proteins—mitotic kinases and kinesins—has the

potential to overcome the limitations related to the role of tubulin in nondividing cells that are associated

with traditional antimitotics. This review concentrates on Polo-like kinase 1, a key regulator of mitosis,

outlines a rationale for its development as an anticancer target, and discusses data from preclinical and

clinical studies of Plk1 inhibitors with a particular focus on NSCLC. Clin Cancer Res; 17(20); 6459–66.

�2011 AACR.

Current Treatment Options

Lung cancer is the second most common malignancy inthe United States (219,440 cases) and was the leading causeof cancer-related mortality (159,390 deaths) in 2009 (1).Non–small cell lung cancer (NSCLC) represents 85% of alllung cancers (2); approximately 40% are diagnosed withadvanced or metastatic disease (3) with a 5-year survivalrate of 14% (4).Chemotherapy with platinum-based doublets (e.g. pac-

litaxel/carboplatin, docetaxel/cisplatin, gemcitabine/cis-platin, and pemetrexed/cisplatin) is the standard of carein first-line treatment of advanced NSCLC with medianoverall survival of approximately 8 months (5) and overallresponse rate of 19% to 30% (5, 6). Combination ofbevacizumab with platinum doublets increases overallresponse rate and prolongs progression-free survival inselected NSCLC patients (7, 8). Second-line treatmentscomprise monotherapies, such as docetaxel (9, 10), peme-trexed (11), or erlotinib (12), and the benefits of theseagents as maintenance therapy are currently debated (13).Erlotinib is recommended for patients who have failedmore than 1 or 2 therapy regimens (12); cytotoxic che-motherapies in such patients are largely ineffective (14).Gefitinib is restricted to second- and third-line patients

currently or previously benefiting from gefitinib or tocertain conditions, such as the presence of epidermalgrowth factor receptor (EGFR)-activating mutations. Clin-ical development of erlotinib and gefitinib—tyrosinekinase inhibitors of EGFR—has opened up the possibilityof these agents in targeted patients whose tumors harboractivating EGFR gene mutations (15, 16). Significantimprovements in response and survival have been reportedwith erlotinib and gefitinib in such patients (17–21).

Novel Approaches Targeting Mitosis

The development of novel agents takes advantage ofrapidly accumulating knowledge of the pathways alteredin cancer cells. Targeting mitosis is a validated approach,and agents that affect the mitotic spindle are well-estab-lished components of many oncotherapeutic regimens,including NSCLC (22). Taxanes (paclitaxel and docetaxel),microtubule-stabilizing agents, Vinca alkaloids (vinorel-bine, vinblastine, etc.), and microtubule-destabilizingagents impair normal mitotic spindle function and blockcellular proliferation (23). New approaches to mitosisinhibition target regulatory proteins—mitotic kinasesand kinesins—that control the process (Fig. 1) and havethe potential to overcome limitations of traditional anti-mitotic agents related to the role of tubulin in normal cells(22). One such target is Polo-like kinase 1 (Plk1), a keyregulator in several essential cell-cycle events, includingmitotic entry, centrosome maturation, bipolar spindle for-mation, chromosome segregation, anaphase-promotingcomplex regulation, and cytokinesis (Fig. 2; ref. 24).

Plk1 in Cancer

Plk1 is the best characterized member of the Plk family(Plk1–5; ref. 25). It is expressed in dividing cells and

Authors' Affiliations: 1Department of Medical Oncology and CancerGenomics Center, University Medical Center Utrecht, Utrecht, The Nether-lands; 2Department of Oncology, and 3Graduate Institute of Oncology andCancer Research Center, National Taiwan University, Taipei, Taiwan

Corresponding Author: James Chih-Hsin Yang, Department of Oncolo-gy, National Taiwan University Hospital, 7 Chung-Shan S. Road, Taipei100, Taiwan. Phone: 886-2-2312-3456 ext 67511; Fax: 886-2-2371-1174;E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-11-0541

�2011 American Association for Cancer Research.

ClinicalCancer

Research

www.aacrjournals.org 6459

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detectable only in proliferating adult tissues (e.g., spleenand testis; ref. 26). High Plk1 levels are a marker ofcellular proliferation (27), observed in NSCLC (28)and other malignancies, including cancers of the breast,colon, endometrium, head and neck, esophagus, ovary,pancreas, prostate, and stomach, as well as glioblastoma,non-Hodgkin lymphoma, leukemia, and melanoma (26,29–31). Plk1 levels in NSCLC tumors correlate inverselywith survival, indicating that Plk1 may have prognostic

value (28); this correlation has also been reported inother tumor types (26, 30, 31). In addition, high tumormitotic rate and risk of metastatic disease have beenassociated with high Plk1 levels (32), implying a rolefor Plk1 in aggressive cancer.

Mechanistic studies using RNA interference (RNAi) haveprovided additional insight into the role of Plk1 in cancercells and the molecular consequences of Plk1 inhibition.Plk1 depletion using siRNA in human cancer cell linesinterrupts spindle assembly and maturation resulting inmitotic (Polo) arrest characterized by scattered chromo-somes on a monopolar spindle and apoptosis (33, 34).This apoptosis is p53 independent; moreover, p53-null or-depleted cells are more sensitive to Plk1 depletion thanwild-type cells (35, 36), suggesting that cancers such asNSCLC with p53 loss of function may be particularlysensitive to Plk1 inhibitors.

Genome-wide RNAi screening has identified Plk1 asan essential survival factor in Ras-driven cells that expe-rience Ras-induced mitotic stress; such cells may beselectively sensitized to Plk-1 inhibition (37). K-ras–activating mutations are common in NSCLC (38) andmay serve as an indicator of better response to Plk1inhibitors. K-ras mutations are found less frequently inthe squamous cell carcinoma histologic subtype (�5%)and more commonly in the adenocarcinoma histologic

Translational Relevance

Targeting the mitotic spindle apparatus leading todisruption of mitosis is a validated approach in cancertreatment. Several novel agents that inhibit proteinregulators of mitosis are undergoing clinical investiga-tion. This review describes inhibitors of a regulator ofmitotic spindle formation, Polo-like kinase 1 (Plk1),introduces the rationale for targeting Plk1 in cancertherapy, and discusses preclinical and early clinical datafrom studies of Plk1 inhibitors, with a particular focuson non–small cell lung cancer (NSCLC). The potentialrole of this novel class of agents in the treatment ofNSCLC and future challenges in their clinical develop-ment are also discussed.

Anaphase Prometaphase

Metaphase

Prophase

Entry intomitosis

Microtubule captureand spindle–pole

separation

Chromosomealignment

Spindle checkpoint

Plk1

Plk1

Plk1CENPE

KSPPlk3

Aurora B

Aurora B

Aurora A

Aurora A

Aurora B

Telophase andcytokinesis

Interphase

Figure 1. Protein effectors of mitosis. KSP, kinesin spindle protein; CENPE, centromeric protein E. Adapted by permission from Macmillan Publishers Ltd.(22). Copyright � 2007.

Medema et al.

Clin Cancer Res; 17(20) October 15, 2011 Clinical Cancer Research6460



subtype (�15%–30%; �25% in Western countries, butless common in Asian populations) of NSCLC.Short hairpin RNAs against Plk1 reduced the growth of

NSCLC A549 cells in mouse tumor xenografts and sup-pressed Plk1 tumor expression (39). Systemic treatmentwith siRNA against Plk1 inhibited the growth of A549 cellsin the mouse liver, showing a role for Plk1 in lung cancerliver metastasis (40). These in vivo studies have confirmedthe anticancer effects of Plk1 depletion in vitro and providea rationale for pharmacologic exploration of Plk1 as anovel target.

Preclinical Studies of Plk1 Inhibitors

Plk1 contains a highly conserved N-terminal proteinkinase domain and a C-terminal "Polo box domain"(PBD) that is required for Plk1 to dock to its intracellulartargets (24, 41). These functionally critical sites havebeen explored in the development of drugs targetingPlk1 (42).

Inhibitors targeting the Polo box domain of Plk1Given the large number of substrates and cellular func-

tions of Plk1, attempts have been made to improve theselectivity of Plk1 inhibitory drugs by targeting the PBD ofPlk1. This has the potential benefit of a higher selectivity forPlk1 over the related Plks and may allow for interference insome, but not all, cellular functions of Plk1. Selective small

drug-like inhibitors of the PBD of Plk1 are purpurogallin(43), poloxin, and thymoquinone (44).

BI 2536. The compound is a dihydropteridinonederivative that shows more than 10,000-fold higherinhibitory potency (IC50 ¼ 0.83 nmol/L) toward Plk1than the majority of 63 other protein kinases tested(45). BI 2536 inhibited proliferation of all 32 examinedhuman cancer cell lines (EC50 ¼ 2–25 nmol/L; ref. 45).Comparable inhibition was also observed in nontrans-formed, immortalized cells, indicating that BI 2536inhibition affects all proliferating cells. Cells treatedwith BI 2536 are blocked in G2–M and form mono-polar mitotic spindles, a phenotype similar to thatinduced by siRNA against Plk1, suggesting that Plk1is the main cellular target (45). BI 2536 (40–50 mg/kg)administered i.v. twice a week inhibited the growthof mouse tumor xenografts, including NSCLC (A549and NCI-H460), and induced accumulation of "Polo-arrested" tumor cells followed by apoptosis, showing BI2536–mediated mitotic arrest and tumor cell deathin vivo (45).

Although cellular sensitivity to BI 2536 was indepen-dent of tumor suppressor or oncogene mutations (45), arecent report has shown that tumor cells and xenograftswith K-ras mutations were more sensitive to BI 2536than isogenic wild-type cells (37). These findings sup-port the hypothesis that Ras-mutant cells may be moredependent on Plk1 for mitotic progression (37). Specific

Prophase

Interphase

Centrosomematuration

Spindleassembly

Cdk1activation Mitotic

entryPlk1

Anaphase

Telophase

Cytokinesis

Cytokinesis

Cdk1inactivation

APC/Cregulation

MetaphasePrometaphase

Figure 2. Functions of Plk1 during mitosis. Adapted by permission from Macmillan Publishers Ltd. (24). Copyright � 2004.

Plk1 Inhibitors in Treatment of NSCLC

www.aacrjournals.org Clin Cancer Res; 17(20) October 15, 2011 6461



pharmacologic agents targeting Plk1 may selectively killRas-mutant cells by exacerbating their mitotic stress andthus benefit patients who bear tumors with activated Rasoncogenes (37).

Volasertib (BI 6727). This dihydropteridinone deriva-tive targets Plk1 with selectivity and efficiency (IC50 ¼ 0.87nmol/L) similar to that of BI 2536 (46). It is also a potentinhibitor of cellular proliferation (EC50 ¼ 11–37 nmol/L)that induces cellular effects (G2–M cell-cycle block, phos-pho-histone H3–positive staining, and monopolar mitoticspindles; ref. 46). Volasertib showed antitumor activity inmouse xenograft models of human cancers, includingNSCLC (NCI-H460), using i.v. or oral administrationschedules of 70 mg/kg/wk or 10 mg/kg/d (46). Notably,it also inhibited taxane-resistant xenograft tumors. Thehigh volume of distribution of volasertib—indicative ofgood tissue penetration, a long terminal half-life in miceand rats, and sustained exposure in tumor tissue (46)—wasan additional factor in the selection of volasertib forpriority clinical development.

GSK461364. This imidazotriazine, ATP-competitive in-hibitor, exhibits more than 1,000-fold higher potency to-ward Plk1 than the majority of 48 other protein kinasestested (47). Cellular treatment withGSK461364 showed notonly signs typical of Plk1 inhibition (mitotic arrest withmonopolar or apolar spindles) but also micronucleationindicative of mitotic slippage, resulting in tetraploidy (47).The extent of mitotic arrest was concentration dependent,and high concentrations (>300 nmol/L) cause a G2 delay.GSK461364 inhibited the growth of a majority of 74 testedcancer cell lines with 89% of the EC50 values lower than 100nmol/L and induced cytotoxic aswell as cytostatic effects thatwere cell line dependent. Intraperitoneal administration ofGSK461364 at various doses induced partial regressions in 2of 3 mouse tumor xenograft models of NSCLC (47).

HMN-176. This stilbene derivative is an active form ofan oral prodrug, HMN-214. HMN-176 disrupts mitoticspindle assembly, inhibits centrosome-dependent micro-tubule nucleation, and is considered an "anticentrosome"agent (48). It does not directly inhibit the enzymaticactivity of Plk1 but rather affects subcellular distributionof Plk1 (49). HMN-176 showed potent cytotoxicity against22 human tumor cell lines (mean IC50 ¼ 118 nmol/L; ref.50). HMN-214 reduced the growth of primary NSCLCtumors in human tumor cloning assay (51) and severaltumor xenografts in mice, including NSCLC (50).

ON 01910.Na. This benzyl styryl sulfone analogue isan ATP-noncompetitive, multitargeted inhibitor of severaltyrosine kinases and cyclin-dependent kinase 1 (Cdk1;IC50¼ 18–260 nmol/L). It is reported to have a particularlystrong potency (IC50 ¼ 9–10 nmol/L) toward Plk1 (52),although results from another report suggest that Plk1 maynot be the primary target (45). ON 01910.Na inhibitedproliferation of more than 100 cell lines, including thoseresistant to paclitaxel, with EC50 in the range of 50 to 250nmol/L. It also showed efficacy with minimal toxicity as amonotherapy or in combinations with cytotoxic drugs inxenograft models (52).

Preclinical studies with Plk1 inhibitors showed thefeasibility and selectivity of a pharmacologic approachto targeting Plk1 as well as the anticipated mode ofaction of inhibitors and their potent antiproliferativeeffects in a majority of cancer cell lines and tumor xeno-grafts. These results led to initiation of clinical studiesand further development of Plk1 inhibitors as anti-cancer drugs.

Clinical Studies of Plk1 Inhibitors

BI 2536A phase I first-in-humans study of BI 2536 was con-

ducted in 40 patients with refractory or metastatic solidtumors previously treated with a median of 3 chemother-apy regimens (53). Most were patients with colorectalcancer (42.5%); the inclusion of patients with NSCLCwas not reported. BI 2536 was administered i.v. once every3 weeks following a dose-escalation design (25–250 mg).Reversible neutropenia with infection was the dose-limit-ing toxicity (DLT) that defined 200 mg as the maximumtolerated dose (MTD). Patients treated at the MTD (67.5%of all treated patients) developed grade 3/4 adverse events(Common Terminology Criteria for Adverse Events, ver-sion 3.0) including neutropenia (55.6%) and leukopenia(44.4%; ref. 53). Similar results were obtained in anotherphase I study of 70 patients with advanced solid cancerstreated with BI 2536 on days 1 and 8 of a 3-week treatmentcourse with MTD of 100 mg (54). Of patients treated with200 mg or more in the once-per-3-weeks regimen, 23%showed stable disease for more than 3 months (53). Thiseffect was more common with patients experiencing neu-tropenia (53).

Two clinical trials have investigated BI 2536 in NSCLC: aphase I study in combination with the antifolate agentpemetrexed (55) and a phase II study of BI 2536 mono-therapy (56). In the combination trial, 33 patients withrefractory or metastatic NSCLC who relapsed after first-lineplatinum-based therapy were treated with 500 mg/m2

pemetrexed and escalating BI 2536 (100–325 mg) by i.v.on day 1 every 3 weeks. Grade 4 neutropenia and grade 3rash were DLTs that established 300 mg as the MTD.Reversible grade 3/4 neutropenia occurred in 18%. Themost common drug-related adverse events were mild tomoderate nausea (36%), rash (33%), anorexia (27%),stomatitis (24%), and pruritus (24%). Two patients hada partial response. BI 2536 and pemetrexed exposures werenot affected by coadministration (55).

In the monotherapy phase II trial, 95 patients withadvanced or metastatic NSCLC who had progressed after,or failed, first- or second-line therapy received either asingle i.v. dose of 200 mg on day 1 or a single i.v. doseof 50 to 60 mg on days 1, 2, and 3 of each treatment course(56). Neutropenia was the main grade 4 adverse event, andmost of the reported adverse events transiently affected thehematopoietic system. Twelve patients had grade 3/4 com-plications associated with neutropenia, including sepsis orfebrile neutropenia (1 patient each) and fever or infection

Medema et al.




associated with low neutrophil counts (10 patients). Fourpatients (4.2%) had an investigator-assessed partial re-sponse (56).

VolasertibA phase I first-in-humans study of volasertib was con-

ducted in 65 patients with advanced solid tumors,including 10 with NSCLC. Volasertib was administeredi.v. once every 3 weeks following a dose-escalation design(12–450 mg; ref. 57). The study reported neutropenia,thrombocytopenia, and febrile neutropenia as DLTs andan MTD of 400 mg. Reversible and noncumulative hema-totoxicity was the major adverse event. Three partialresponses were observed in patients with urothelial andovarian cancer and melanoma, and stable disease wasreported in 48% (57). The study reported favorable phar-macokinetic parameters (linearity in the therapeutic doserange, large volume of drug distribution, and a half-lifearound 110 hours). A phase I trial of volasertib admin-istered on days 1 and 8 every 21 days is currently ongoing(NCT00969553; ref. 58). These results prompted theinitiation of multiple phase II studies, including a ran-domized trial of volasertib as monotherapy or in com-bination with pemetrexed in second-line NSCLC(NCT00824408).The identification of neutropenia as the dominant

adverse event in studies with BI 2536 and volasertibindicates a mechanism-based inhibition of bone marrowcellular proliferation. In addition, the absence of anyreported cumulative or high-grade mucosal side effectssuggests the feasibility of prolonged BI 2536 or volasertibadministration.Although the clinical development of BI 2536 has

been halted, volasertib is currently being investigatedas a single agent in phase II trials in several differentindications (NCT01023958 and NCT01121406) and as acombination with platinum (NCT00969761), peme-trexed (NCT00824408), or other targeted therapies(NCT01022853 and NCT01206816).

GSK461364A phase I first-in-humans study of GSK461364 was

conducted in 27 patients with advanced solid tumors(59). The agent was administered i.v. following 2 sche-dules with different dosing (50–225 mg on days 1, 8, and15 or 25–100 mg on days 1, 2, 8, 9, 15, and 16) on a 28-day cycle. DLTs included grade 4 neutropenia, sepsis, orpulmonary embolism. Common adverse events includedhematologic toxicity, phlebitis, nausea, and fatigue. Sta-ble disease for more than 5 months was observed in 2patients. GSK461364 increased phospho-histone H3levels in circulating tumor cells, indicating antimitoticeffects of the treatment. The recommended phase II dosefor GSK461364 was 225 mg on days 1, 8, and 15 in a 28-day cycle. Because of the high incidence (20%) of venousthromboembolism, GSK461364 should involve coad-ministration of prophylactic anticoagulation for furtherclinical evaluation (59).

HMN-214Two phase I studies of HMN-214 have been reported

in patients with solid tumors (49, 60). DLTs of pro-longed neutropenia, febrile neutropenia, neutropenicsepsis, electrolyte disturbance, neuropathy, and myalgiawere observed at doses of 24 to 48 mg/m2 for 5 conse-cutive days every 4 weeks. MTD was established at therange of 18 to 30 mg/m2, based on previous patienttreatment load (60).

In another study, 33 patients with advanced cancerreceived oral HMN-214 (3.0–9.9 mg/m2/d) in a continu-ous 21-day dosing schedule every 28 days (49). DLTscomprised severe myalgia and/or bone pain syndromeand hyperglycemia. MTD was 8.0 mg/m2/d. The studyreported 24% of patients with stable disease and indicatedthat future development of HMN-214 would focus onpatient populations with high tumor expression of Plk1.

ON 01910.NaA phase I first-in-humans study of ON 01910.Na was

conducted in 20 patients with advanced solid tumors(none with NSCLC; ref. 61). The agent was administeredi.v. at 80 to 4,370mg by accelerated titration design on days1, 4, 8, 11, 15, and 18 in 28-day cycles. Grade 3 abdominalpain was reported as a DLT at an MTD of 3,120 mg. Themost frequently reported adverse events (grade �3) duringthe first treatment cycle comprised skeletal, abdominal,and tumor pain; nausea and vomiting; urge to defecate;flatulence; and fatigue. Mild hematologic toxicity—anemiaand lymphopenia—was reported in approximately 10% ofpatients, and this contrasts with other Plk1-targeting com-pounds. One partial response was observed in a patientwith ovarian cancer (61).

Although early preclinical studies identified Plk1 asa main target of ON 01910.Na (52), its mode of actionremains unknown (45). Current clinical studies ofthis agent concentrate on ovarian cancer and hemato-logic malignancies, with some ongoing phase I studiesinvestigating ON 01910.Na as monotherapy or in com-bination with chemotherapies in patients with solidtumors. Its development in NSCLC in the near futureis unlikely.

Of the Plk inhibitors discussed here, we believe thatvolasertib has several possible advantages. These includeits high volume of distribution, long terminal half-life, andearly signs of antitumor efficacy in single-agent studies (57,58). However, because all of these agents are at an earlydevelopment stage (Table 1), further clinical data arerequired to determine their potential.

The future investigation of Plk inhibitors should focuson combinations with chemotherapies. First, the tumorresponse to Plk inhibitors as a single agent appearslimited. Second, biomarkers predictive of response toPlk inhibitors as a single agent have not been availableso far. Third, the main side effect of Plk inhibitors isreversible, uncomplicated myelosuppression. Therefore,it is possible to combine a Plk inhibitor with otherchemotherapeutic agent(s).





Conclusions

Monotherapy with Plk1 inhibitors, as demonstrated inphase I/II studies, has shown manageable, noncumulative,and predominantly hematologic toxicity that correlateswith the predicted mode of action of agents. Preliminarysigns of antitumor activity have been shown, althoughmuch work needs to be done to optimize treatment regi-mens, identify agents with potentially synergistic activity,and define markers of tumor response and patient char-acteristics that predict therapeutic success. Future clinicalstudies should include the detection of pharmacodynamicbiomarkers, such as phospho-histone H3, to validate Plk1as the tumor target. In the first-in-humans phase I study ofGSK461364 in advanced solid tumors, Plk1 inhibition intumor cells was confirmed on the basis of the analysis ofphospho-histone H3 expression in circulating tumor cells(59). Other promising biomarker assays for Plk1 inhibitionin vivohave been developed, such as an immunohistochem-ical approach that measures serine 46-phosphorylation ofthe translational controlled tumor protein by Plk1 (62)and an ELISA-based assay that measures phosphorylationof the PBD-binding protein 1 (PBIP1, also known as MLF1or CENP-U) by Plk1 (63). Patient stratification based onPlk1 expression should be considered in future trials;NSCLC patients with poor prognosis whose tumors express

high levels of Plk1 may be good candidates for Plk1-target-ing therapy. Preclinical studies have shown that p53 and/orRas-mutant cells may be more sensitive to Plk1 inhibitors.This hypothesis, relevant for several solid tumors (e.g.,ovarian cancer and urothelial carcinoma), but particularlyfor NSCLC, also needs to be clinically validated.

Disclosure of Potential Conflicts of Interest

The authors received no compensation related to the developmentof the manuscript. Chia-Chi Lin and James Chih-Hsin Yang are onthe Advisory Board of Boehringer Ingelheim and did not receive anyhonorarium.

Authors' Contributions

The authors meet criteria for authorship as recommended by the Inter-national Committee of Medical Journal Editors, were fully responsible forall content and editorial decisions, and were involved in all stages ofmanuscript development.

Grant Support

Writing and editorial assistance was provided by Ogilvy Healthworld,which was contracted by Boehringer Ingelheim Pharma GmbH & Co., KGfor these services.

Received February 27, 2011; revised June 14, 2011; accepted July 14,2011; published online October 14, 2011.

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Table 1. Plk inhibitors in clinical development

Compound Company Mode of action DLT Efficacy Status References

BI 2536 BoehringerIngelheim

Plk1 inhibitor Neutropenia PR in phase II Phase II(halted)

53–56

Volasertib(BI 6727)

BoehringerIngelheim

Plk1 inhibitor Neutropenia,thrombocytopenia

DurablePR in phase I

Phase I/II 57, 58

GSK461364 GlaxoSmithKline Plk1 inhibitor Neutropenia,thrombocytopenia,pulmonary emboli

ProlongedSD in phase I

Phase I 59

HMN-214 NipponShinyakuCo. Ltd.

Plk1 interference,not direct inhibitor

Muscle/bone pain,hyperglycemia

ProlongedSD in phase I

Phase I 60

ON 01910.Na OnconovaTherapeutics, Inc.

Plk1 inhibitor,Cdk inhibitor,ERK inhibitor,PI3K inhibitor,AKT inhibitor

Abdominal pain ProlongedSD in phase I

Phase I 61

Abbreviations: PR, partial response; SD, stable disease; ERK extracellular signal-regulated kinase; PI3K, phosphoinositide 3-kinase.

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Medema et al.




2011;17:6459-6466. Clin Cancer Res René H. Medema, Chia-Chi Lin and James Chih-Hsin Yang Therapy, with a Focus on NSCLCPolo-like Kinase 1 Inhibitors and Their Potential Role in Anticancer

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