volasertib and Carcinoma--Non-Small-Cell-Lung

Second-line therapy options that improve survival for patients with advanced non-small-cell lung cancer (NSCLC) are needed. This randomized, phase II trial (n [ 143) investigated volasertib monotherapy or in combination with pemetrexed compared with pemetrexed monotherapy in patients with NSCLC whose disease had progressed after previous platinum-based chemotherapy. The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy.. Volasertib is a potent, selective, cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In this study we compared volasertib, volasertib with pemetrexed, and pemetrexed alone in patients with advanced non-small-cell lung cancer (NSCLC) whose disease progressed after first-line platinum-based chemotherapy.. A run-in phase (n = 12) was used to determine whether volasertib could be combined in full dose with pemetrexed 500 mg/m(2). Subsequent patients were randomized to volasertib (n = 37), volasertib with pemetrexed (n = 47), or pemetrexed (n = 47) administered on day 1 every 21 days. The primary end point was progression-free survival (PFS); secondary end points included objective response rate and pharmacokinetics.. Volasertib 300 mg was chosen for the randomized phase. Recruitment to single-agent volasertib was stopped early because of lack of efficacy. Median PFS was 5.3 months with pemetrexed compared with 3.3 months with volasertib with pemetrexed (hazard ratio [HR], 1.141; 95% confidence interval [CI], 0.73-1.771) and 1.4 months with volasertib (HR, 2.045; 95% CI, 1.27-3.292). ORRs were 10.6% with pemetrexed, 21.3% for volasertib with pemetrexed, and 8.1% with volasertib. The most common all-grade related adverse events (pemetrexed/volasertib with pemetrexed/volasertib) were: fatigue (28 [61%]/27 [59%]/11 [31%]), nausea (21 [46%]/19 [41%]/0 [0%]), decreased apetite (14 [31%]/13 [28%]/2 [6%]), neutropenia (4 [9%]/8 [17%]/9 [25%]), rash (9 [20%]/8 [17%]/2 [6%]), vomiting (6 [13%]/13 [28%]/0 [0%]), and diarrhea (8 [17%]/11 [24%]/0 [0%]). Pharmacokinetics analyses showed no drug-drug interactions between volasertib and pemetrexed.. For treatment in the second-line for advanced or metastatic NSCLC, the combination of volasertib with standard pemetrexed did not increase toxicity significantly but also did not improve efficacy compared with single-agent pemetrexed.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Drug Dosage Calculations; Drug Interactions; Drug Resistance, Neoplasm; Drug Therapy, Combination; Fatigue; Female; Humans; Lung Neoplasms; Male; Middle Aged; Nausea; Pemetrexed; Platinum Compounds; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Survival Analysis

NRAS mutation is rarely observed in non-small cell lung cancer (NSCLC) patients, and there are no approved treatments for NRAS-mutant NSCLC. Here, we evaluated the effect of pan-RAF inhibitors on human NRAS-mutant NSCLC cell lines and performed high-throughput screening using human kinome small interfering (si)RNA or CRISPR/Cas9 libraries to identify new targets for combination NSCLC treatment. Our results indicate that human NRAS-mutant NSCLC cells are moderately sensitive to pan-RAF inhibitors. High-throughput kinome screenings further showed that G2/M arrest, particularly following knockdown of polo-like kinase 1 (PLK1), can inhibit the growth of human NRAS-mutant NSCLC cells and those treated with the type II pan-RAF inhibitor LXH254. In addition, treatment with volasertib plus LXH254, resulting in dual blockade of PLK1 and pan-RAF, was found to be more effective than LXH254 monotherapy for inhibiting long-term cell viability, suggesting that this combination therapeutic strategy may lead to promising results in the clinic.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; GTP Phosphohydrolases; High-Throughput Screening Assays; Humans; Lung Neoplasms; Male; Membrane Proteins; Mutation; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Pteridines

Topics: A549 Cells; Apoptosis; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Hypoxia; Gene Knockdown Techniques; Humans; Lung Neoplasms; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Tumor Suppressor Protein p53

To address the need for improved systemic therapy for non-small-cell lung cancer (NSCLC), we previously demonstrated that mesenchymal NSCLC was sensitive to polo-like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cMet was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cMet phosphorylation only in mesenchymal cells. Constitutively active cMet abrogates Plk1 inhibitor-induced apoptosis. Likewise, cMet silencing or inhibition enhances Plk1 inhibitor-induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cMet activation after Plk1 inhibition. In four animal NSCLC models, mesenchymal tumors were more sensitive to Plk1 inhibition alone than were epithelial tumors. The combination of cMet and Plk1 inhibition led to regression of tumors that did not regrow when drug treatment was stopped. Plk1 inhibition did not affect HGF levels but did decrease vimentin phosphorylation, which regulates cMet phosphorylation via β1-integrin. This research defines a heretofore unknown mechanism of ligand-independent activation of cMet downstream of Plk1 and an effective combination therapy.

Topics: Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Drug Resistance, Neoplasm; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Humans; Integrin beta1; Lung Neoplasms; Mice, Nude; Phenotype; Phosphorylation; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Pteridines; Transforming Growth Factor beta; Vimentin; Xenograft Model Antitumor Assays

To assure faithful chromosome segregation, cells make use of the spindle assembly checkpoint, which can be activated in aneuploid cancer cells. In this study, the efficacies of inhibiting polo-like kinase 1 (PLK1) on the radiosensitization of non-small-cell lung cancer (NSCLC) cells were studied. Clonogenic survival assay was performed to identify the effects of the PLK1 inhibitor on radiosensitivity within NSCLC cells. Mitotic catastrophe assessment was used to measure the cell death and histone H2AX protein (γH2AX) foci were utilized to assess the DNA double-strand breaks (DSB). The transcriptome was analyzed via unbiased profiling of microarray expression. The results showed that the postradiation mitotic catastrophe induction and the DSB repair were induced by PLK1 inhibitor BI-6727, leading to an increase in the radiosensitivity of NSCLC cells. BI-6727 in combination with radiation significantly induced the delayed tumor growth. PLK1-silenced NSCLC cells showed an altered mRNA and protein expression related to DNA damaging, replication, and repairing, including the DNA-dependent protein kinase (DNAPK) and topoisomerase II alpha (TOPO2A). Furthermore, inhibition of PLK1 blocked 2 important DNA repair pathways. To summarize, our study showed PLK1 kinase as an option in the therapy of NSCLC.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Chromosome Segregation; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication; Humans; Lung Neoplasms; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial-mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Disease-Free Survival; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms; Mice; Mice, Nude; Mutation; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Xenograft Model Antitumor Assays

Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel mitosis-specific agents with higher selectivity than approved tubulin-binding agents (taxanes, Vinca alkaloids), we have generated inhibitors of Polo-like kinase 1, a target that functions predominantly in mitosis.. The first compound in this series, suitable for i.v. administration, has entered clinical development. To fully explore the potential of Polo-like kinase 1 inhibition in oncology, we have profiled additional compounds and now describe a novel clinical candidate.. BI 6727 is a highly potent (enzyme IC(50) = 0.87 nmol/L, EC(50) = 11-37 nmol/L on a panel of cancer cell lines) and selective dihydropteridinone with distinct properties. First, BI 6727 has a pharmacokinetic profile favoring sustained exposure of tumor tissues with a high volume of distribution and a long terminal half-life in mice (V(ss) = 7.6 L/kg, t(1/2) = 46 h) and rats (V(ss) = 22 L/kg, t(1/2) = 54 h). Second, BI 6727 has physicochemical and pharmacokinetic properties that allow in vivo testing of i.v. as well as oral formulations, adding flexibility to dosing schedules. Finally, BI 6727 shows marked antitumor activity in multiple cancer models, including a model of taxane-resistant colorectal cancer. With oral and i.v. routes of administration, the total weekly dose of BI 6727 is most relevant for efficacy, supporting the use of a variety of well-tolerated dosing schedules.. These findings warrant further investigation of BI 6727 as a tailored antimitotic agent; clinical studies have been initiated.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Crystallography, X-Ray; Enzyme Inhibitors; Female; Fluorescent Antibody Technique; Forkhead Transcription Factors; Humans; Immunoenzyme Techniques; Lung Neoplasms; Mice; Mice, Nude; Polo-Like Kinase 1; Protein Conformation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Rats; Rats, Wistar; Tissue Distribution; Xenograft Model Antitumor Assays