volasertib and Neoplasms

The polo-like kinases (Plks) encompass a family of five serine/threonine protein kinases that play essential roles in many cellular processes involved in the control of the cell cycle, including entry into mitosis, DNA replication and the response to different types of stress. Plk1, which has been validated as a cancer target, came into the focus of many pharmaceutical companies for the development of small-molecule inhibitors as anticancer agents. Recently, FDA (Food and Drug Administration) has granted a breakthrough therapy designation to the Plk inhibitor BI 6727 (volasertib), which provided a survival benefit for patients suffering from acute myeloid leukemia. However, the various ATP-competitive inhibitors of Plk1 that are currently in clinical development also inhibit the activities of Plk2 and Plk3, which are considered as tumor suppressors. Plk3 contributes to the control and progression of the cell cycle while acting as a mediator of apoptosis and various types of cellular stress. The aberrant expression of Plk3 was found in different types of tumors. Recent progress has improved our understanding of Plk3 in regulating stress signaling and tumorigenesis. When using ATP-competitive Plk1 inhibitors, the biological roles of Plk1-related family members like Plk3 in cancer cells need to be considered carefully to improve treatment strategies against cancer.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Carcinogenesis; Cell Cycle Proteins; DNA Damage; Humans; Molecular Targeted Therapy; Neoplasms; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Proto-Oncogene Proteins; Pteridines; Tumor Suppressor Proteins

Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Proteins; Humans; Neoplasms; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Randomized Controlled Trials as Topic

Owing to their integral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, has emerged as an attractive therapeutic target in oncology. In recent years, several Plk1 inhibitors have been developed, with some agents showing encouraging results in early-phase clinical trials. This review focuses on volasertib (BI 6727; an investigational agent), a potent and selective Plk inhibitor. Volasertib has shown promising activity in various cancer cell lines and xenograft models of human cancer. Trials performed to date suggest that volasertib has clinical efficacy in a range of malignancies, with the most promising results seen in patients with acute myeloid leukemia (AML). Encouragingly, recent phase II data have demonstrated that volasertib combined with low-dose cytarabine (LDAC) was associated with higher response rates and improved event-free survival than LDAC alone in patients with previously untreated AML. Based on these observations, and its presumably manageable safety profile, volasertib is currently in phase III development as a potential treatment for patients with AML who are ineligible for intensive remission induction therapy. Given that many patients with AML are of an older age and frail, this constitutes an area of major unmet need. In this review, we discuss the biologic rationale for Plk1 inhibitors in cancer, the clinical development of volasertib to date in solid tumors and AML, and the future identification of biomarkers that might predict response to volasertib and help determine the role of this agent in the clinic.

Topics: Humans; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pteridines

Significant advances in cancer treatment have resulted from the targeted cancer therapy by understanding the process of malignant transformation. Polo-like kinase 1 (PLK1) has been investigated as a target for cancer therapy for several years. Recently, anticancer drug candidates targeting PLK1 have been developed. To investigate the significance of PLK1 inhibitors in cancer patients, the current clinical statuses of PLK1 inhibitors including BI 2536, volasertib, and GSK461364A were analyzed. Monotherapy with BI 2536, the first human study of PLK1 inhibitors, has been terminated now, but its combinational study is still available in several solid tumors. The second-generation PLK1 inhibitor volasertib has an improved pharmacokinetic profile, safety, and efficacy, which is currently being developed under phase I/II. GSK461364 has shown a greater sensitive antitumor effect in p53-mutated cancer compared with that of p53-wild type cancer cells in a preclinical study. However, it has to be coadministered with an anticoagulator because of the high incidence of venous thrombotic emboli in clinical studies. PLK1 inhibitors showed a favorable pharmacokinetic profile, safety, and efficacy in patients with solid tumors. Further investigation with the use of PLK1 inhibitors in cancer patients who have mutated p53 or Ras and a high level of PLK1 as biomarkers is needed to consider the context and evaluation criteria of therapy.

Topics: Animals; Antineoplastic Agents; Cell Cycle Proteins; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Neoplasms; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Thiophenes

Polo-like kinases (PLKs) are a group of highly conserved serine/threonine protein kinases that play a key role in processes such as cell division and checkpoint regulation of mitosis. About 80% of human tumors, of various origins, express high levels of PLK transcripts. However, PLK mRNA is mostly absent in surrounding healthy tissues. Overexpression of PLK is associated with a poor prognosis in several tumor types and a lower overall survival rate. The overexpression of PLKs in human tumors, but not in healthy nondividing cells, makes them an attractive, selective target for cancer drug development. PLK inhibitors interfere with different stages of mitosis, such as centrosome maturation, spindle formation, chromosome separation, and cytokinesis. They induce mitotic chaos and severely perturb cell cycle progression, eventually leading to cancer cell death. Several PLK inhibitors are in development and are undergoing evaluations as potential cancer treatments. This review includes an overview of PLK inhibitors in early clinical development (i.e., BI 2536, BI 6727, GSK461364, ON 019190.Na, and HMN-214) and in advanced preclinical development (i.e., ZK-thiazolidinone, NMS-1, CYC-800, DAP-81, and LC-445). If proof of principle is confirmed in large studies, PLK inhibitors will offer a new targeted antitumor therapy for cancer patients.

Topics: Aniline Compounds; Animals; Cell Cycle Proteins; Clinical Trials as Topic; Cyclic N-Oxides; Drug Evaluation, Preclinical; Glycine; Humans; Neoplasms; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Pyridines; Sulfonamides; Sulfones; Thiazolidines

This drug-drug interaction study determined whether the metabolism and distribution of the Polo-like kinase 1 inhibitor, volasertib, is affected by co-administration of the P-glycoprotein and cytochrome P-450 3A4 inhibitor, itraconazole.. This was an uncontrolled, open-label, fixed-sequence trial of two 21-day treatment cycles in patients with various solid tumors. In cycle 1 (test), eligible patients were administered volasertib (day 1) plus itraconazole (days -3 to 15). In cycle 2 (reference), patients received volasertib monotherapy. The primary end point was the influence of co-administration of itraconazole on the pharmacokinetic profile (AUC. Concurrent administration of itraconazole resulted in a slight reduction in the AUC. While there was no clear evidence of a pharmacokinetic interaction between volasertib and itraconazole, co-administration reduced the tolerability of volasertib. Clinicaltrials.gov identifier: NCT01772563.

Topics: Adult; Aged; Antineoplastic Agents; Cell Cycle Proteins; Drug Interactions; Female; Humans; Itraconazole; Male; Middle Aged; Neoplasms; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines

This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical effects of volasertib, a selective Polo-like kinase inhibitor that induces mitotic arrest and apoptosis, in Japanese patients with advanced solid tumors (NCT01348347; 1230.15).. In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) received volasertib (200-350 mg) as a single dose by intravenous infusion over 2 h on day 1 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the MTD of volasertib in Japanese patients with an advanced solid tumor; secondary endpoints included safety, pharmacokinetics, and clinical benefit.. Fifteen patients with an advanced solid tumor were treated. Dose-limiting toxicities of grade 4 neutropenia for ≥7 days and grade 4 thrombocytopenia were both experienced by 2/6 patients in the 350 mg cohort. The MTD of volasertib in Japanese patients was 300 mg. The most common (≥3 patients) drug-related non-hematologic adverse events included fatigue, decreased appetite, and nausea. Exposure to volasertib and its metabolite increased with increasing doses. A partial response in a patient with gastric cancer and stable disease in eleven patients were observed.. Volasertib had a manageable safety profile up to the MTD determined as 300 mg. Exposure to volasertib and its metabolite increased with increasing doses. The safety profile of volasertib in Japanese patients is comparable with those previously obtained in Caucasian patients. These data support enrollment of Japanese patients in global clinical trials without dose modification.

Topics: Adult; Aged; Antineoplastic Agents; Asian People; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Pteridines

This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6).. Sequential patient cohorts (3 + 3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m(2)) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n = 30) or volasertib/carboplatin (n = 31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively.. The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m(2) and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively.. Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cell Cycle Proteins; Cisplatin; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Platinum; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Young Adult

To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, combined with afatinib, an oral irreversible ErbB family blocker, in patients with advanced solid tumors (NCT01206816; Study 1230.20).. Patients with advanced non-resectable and/or metastatic disease following failure of conventional treatment received intravenous volasertib 150-300 mg on day 1 every 21 days, combined with oral afatinib 30-40 mg on days 2-21 of a 3-week cycle (Schedule A), or 50-90 mg on days 2-6 of a 3-week cycle (Schedule B). The primary objective was to determine the MTD of volasertib in combination with afatinib.. Fifty-seven patients (Schedule A, N = 29; Schedule B, N = 28) were treated. The MTDs were volasertib 300 mg plus afatinib 30 mg days 2-21 and 70 mg days 2-6 of a 3-week cycle for Schedules A and B, respectively. The most common Grade 3/4 adverse events were neutropenia (31.0 %), diarrhea (13.8 %), and thrombocytopenia (10.3 %) in Schedule A; neutropenia (39.3 %), thrombocytopenia (35.7 %), hypokalemia (14.3 %), febrile neutropenia, and nausea (each 10.7 %) in Schedule B. The best overall response was two partial responses (6.9 %; both in Schedule A); eight patients in each schedule achieved stable disease. Volasertib showed multi-exponential pharmacokinetic (PK) behavior; co-administration of volasertib and afatinib had no significant effects on the PK profile of either drug.. Volasertib combined with afatinib had manageable adverse effects and limited antitumor activity in this heavily pretreated population.

Topics: Administration, Oral; Adult; Afatinib; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Female; Humans; Infusions, Intravenous; Male; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Neutropenia; Protein Kinase Inhibitors; Pteridines; Quinazolines; Severity of Illness Index; Thrombocytopenia

Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors.. This open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230.7). Volasertib was administered by intravenous infusion over 2 h, starting at 100 mg in the first dose cohort. Nintedanib was administered orally at a dose of 200 mg twice daily. The first treatment cycle comprised 28 days (days 1-7 and days 9-28: nintedanib; day 8: volasertib). From cycle 2 onwards, volasertib was administered on day 1 of a 21-day cycle and nintedanib was administered days 2-21. The primary objective was the MTD of volasertib in combination with nintedanib.. Thirty patients were treated. The MTD of volasertib plus fixed-dose nintedanib was 300 mg once every 3 weeks, the same as the recommended single-agent dose of volasertib in solid tumors. Two of 12 assessable patients treated with the MTD experienced dose-limiting toxicities [grade 3 increased alanine aminotransferase (ALT); grade 3 ALT increase and grade 3 increased aspartate aminotransferase]. Disease control [stable disease (SD)/partial response (PR)/complete response (CR)] was achieved in 18 patients (60%): 1 CR (breast cancer), 1 PR (nonsmall-cell lung cancer), and 16 patients with SD. Volasertib showed that multiexponential pharmacokinetic behavior and co-administration of nintedanib had no significant effects on its exposure.. Volasertib could be combined with fixed-dose nintedanib at the recommended single-agent dose. At this dose, the combination had a manageable safety profile without unexpected or overlapping adverse events, and showed antitumor activity.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Pteridines

Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours.. Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course.. Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ∼135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile.. These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients.

Topics: Adult; Aged; Antineoplastic Agents; Cell Cycle Proteins; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Hematologic Diseases; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Proteins; Neoplasms; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Salvage Therapy; Taiwan; Treatment Outcome

Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters.. This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12-450 mg.. Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3: 8%), neutropenia (15%; grade 3/4: 14%), fatigue (15%; grade 3: 2%), and thrombocytopenia (14%; grade 3/4: 14%) were the most frequent drug-related adverse events. The MTD was 400mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from 'dose-linear PK' behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (~111 h).. This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing.

Topics: Adult; Aged; Antineoplastic Agents; Cohort Studies; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Pteridines; Young Adult

Dysfunctions in post-transcriptional control are observed in cancer and chronic inflammatory diseases. Here, we employed a kinome inhibitor library (n = 378) in a reporter system selective for 3'-untranslated region-AU-rich elements (ARE). Fifteen inhibitors reduced the ARE-reporter activity; among the targets is the polo-like kinase 1 (PLK1). RNA-seq experiments demonstrated that the PLK1 inhibitor, volasertib, reduces the expression of cytokine and cell growth ARE mRNAs. PLK1 inhibition caused accelerated mRNA decay in cancer cells and was associated with reduced phosphorylation and stability of the mRNA decay-promoting protein, tristetraprolin (ZFP36/TTP). Ectopic expression of PLK1 increased abundance and stability of high molecular weight of ZFP36/TTP likely of the phosphorylated form. PLK1 effect was associated with the MAPK-MK2 pathway, a major regulator of ARE-mRNA stability, as evident from MK2 inhibition, in vitro phosphorylation, and knockout experiments. Mutational analysis demonstrates that TTP serine 186 is a target for PLK1 effect. Treatment of mice with the PLK1 inhibitor reduced both ZFP36/TTP phosphorylation in xenograft tumor tissues, and the tumor size. In cancer patients' tissues, PLK1/ARE-regulated gene cluster was overexpressed in solid tumors and associated with poor survival. The data showed that PLK1-mediated post-transcriptional aberration could be a therapeutic target.

Topics: 3' Untranslated Regions; Animals; Cell Cycle Proteins; Humans; Mice; Mice, Nude; Neoplasms; Phosphorylation; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; RNA Processing, Post-Transcriptional; Tristetraprolin; Xenograft Model Antitumor Assays

USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels of USP7, especially in taxane-resistant cancer. USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix. Depletion of USP7 induced multiple spindle pole formation in mitosis, and, consequently, resulted in mitotic catastrophe. When USP7 was blocked in the paclitaxel-resistant lung cancer NCI-H460

Topics: A549 Cells; Cell Cycle Proteins; Drug Resistance, Neoplasm; Humans; Neoplasms; Paclitaxel; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Thiophenes; Ubiquitin-Specific Peptidase 7

Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies.. Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib.. Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide.. These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Bone Neoplasms; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Child; Drug Synergism; Female; Flow Cytometry; Humans; Medulloblastoma; Mice; Mice, Nude; Neoplasms; Neuroblastoma; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Rhabdomyosarcoma; Sarcoma, Ewing; Tumor Cells, Cultured; Vincristine; Xenograft Model Antitumor Assays

Exposure to drugs that interfere with microtubule dynamics block cell cycle progression at mitosis by prolonged activation of the spindle assembly checkpoint (SAC). Cells can evade mitotic arrest and proceed to interphase without chromosome segregation by a process termed mitotic slippage that involves Cyclin B1 degradation without checkpoint inactivation. Here, we explored the cellular response to small-molecule inhibitors of Polo-like kinase 1 (Plk1), an important regulator of cell division. We found that the clinical Plk1 inhibitors BI 2536 and BI 6727, both unexpectedly, induced a dose-dependent cellular drug response: While mitotic arrest was induced in cancer cell lines and primary non-transformed cells across the entire range of concentrations tested, only high concentrations seemed to promote mitotic slippage. Since this observation contrasts with the effects expected from studies reporting RNAi-mediated Plk1 depletion in cancer cells, we wondered whether both ATP-competitive inhibitors target unknown kinases that are involved in signaling from the spindle assembly checkpoint (SAC) and might contribute to the mitotic slippage. A chemical proteomics approach used to profile the selectivity of both inhibitors revealed that SAC kinases are not targeted directly. Still, the activities of Cdk1/Cyclin B1 and Aurora B, which plays important roles in the error correction of false microtubule-kinetochore attachments and in checkpoint signaling, were shown to be downregulated at high inhibitor concentrations. Our data suggest that the inhibition of Plk1 activity below a certain threshold influences Aurora B activity via reduced phosphorylation of Fox M1 and Survivin leading to diminished levels of Aurora B protein and alteration of its subcellular localization. Within the spectrum of SAC proteins that are degraded during mitotic slippage, the degradation of Cyclin B1 and the downregulation of Aurora B activity by Plk1 inhibition seem to be critical promoters of mitotic slippage. The results indicate that careful dose-finding studies in cancer trials are necessary to limit or even prevent mitotic slippage, which could be associated with improved cancer cell survival.

Topics: Cell Cycle Proteins; Cell Line, Tumor; Female; Human Umbilical Vein Endothelial Cells; Humans; M Phase Cell Cycle Checkpoints; Male; Neoplasm Proteins; Neoplasms; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines

The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) is associated with poor prognosis in many types of cancer. Consequently, Plk1 has emerged as a valid therapeutic target for anticancer drug design. Volasertib is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting cell cycle arrest at nanomolar concentrations. However, the risk of developing drug resistance, which is often associated with the overexpression of the ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein), can present a therapeutic challenge for volasertib and many other therapeutic drugs. Although volasertib is highly effective against the proliferation of numerous cancer cell lines, we found that the overexpression of ABCB1 in cancer cells leads to cellular resistance to volasertib and reduces the level of volasertib-stimulated G2/M cell cycle arrest and subsequent onset of apoptosis. Furthermore, we demonstrate that volasertib competitively inhibits the function of ABCB1 and stimulates the basal ATPase activity of ABCB1 in a concentration-dependent manner, which is consistent with substrate transport by ABCB1. More importantly, we discovered that the coadministration of an inhibitor or drug substrate of ABCB1 restored the anticancer activity of volasertib in ABCB1-overexpressing cancer cells. In conclusion, the results of our study reveal that ABCB1 negatively affects the efficacy of volasertib and supports its combination with a modulator of ABCB1 to improve clinical responses.

Topics: Adenosine Triphosphatases; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Blotting, Western; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Drug Resistance, Neoplasm; Humans; Neoplasms; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines

Polo-like kinase 1 (PLK1) plays an important role in mitotic progression, is frequently overexpressed and associated with a poor prognosis of cancer patients, thus providing a promising target in anticancer treatment. Aim of the current project was to evaluate the effect of the novel PLK1 inhibitor BI 6727 in combination with irradiation.. In vitro proliferation and radiation cell survival assays as well as in vivo local tumour control assays after single treatment and combined radiation and drug application were carried out using the squamous cell carcinoma models A431 and FaDu. In addition, cell cycle phases were monitored in vitro and in vivo.. BI 6727 showed a dose-dependent antiproliferative effect and an increase in the mitotic fraction. BI 6727 alone reduced clonogenic cell survival, while radiosensitivity in vitro (SF2) and in vivo (single-dose TCD(50) under clamped hypoxia) was not affected. In contrast, local tumour control was significantly improved after application of BI 6727 simultaneously to fractionated irradiation (A431: TCD(50) = 60.5 Gy [95% C.I. 57; 63] after IR alone and <30 Gy after combined treatment; FaDu: 49.5 Gy [43; 56 Gy] versus 32.9 Gy [26; 40]).. Despite the lack of direct cellular radiosensitisation, PLK1 inhibition with BI 6727 during fractionated irradiation significantly improves local tumour control when compared to irradiation alone. This result is likely explained by a considerable effect on cell cycle and an independent cytotoxic potential of BI 6727.

Topics: Animals; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Female; Humans; Male; Mice; Neoplasms; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Radiation-Sensitizing Agents