Comprehensive biomarker analyses in patients with advanced or metastatic non-small cell lung cancer prospectively treated with the polo-like Kinase 1 Inhibitor BI2536
Autor: | Martin Schuler, Beatrice Wehler, Kurt Werner Schmid, Martin Sebastian, J. Wohlschläger, Stefan Kasper, Daniela Westerwick, Birgit Gaschler-Markefski, Arno Schad, Gerd Munzert, Martin Werner, Karl Worm, Alicia Morresi-Hauf, Joachim von Pawel, Saskia Ting, Frank Breitenbuecher, Cornelius Kortsik |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty Lung Neoplasms DNA Mutational Analysis Medizin Phases of clinical research Antimitotic Agents medicine.disease_cause PLK1 Disease-Free Survival Cohort Studies Proto-Oncogene Proteins p21(ras) 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Internal medicine Biomarkers Tumor Medicine Prospective Studies Biomarker Analysis Neoplasm Metastasis Lung cancer Protein kinase B business.industry Pteridines Sequence Analysis DNA Hematology medicine.disease Up-Regulation 030104 developmental biology 030220 oncology & carcinogenesis Disease Progression Cancer research Immunohistochemistry Biomarker (medicine) KRAS business |
Popis: | Background: Polo like kinase 1 (PLK1) is frequently upregulated in tumors and is thus viewed as a promising therapeutic target in various cancers. Several PLK1 inhibitors have recently been developed and clinically tested in solid cancers, albeit with limited success. So far, no predictive biomarkers for PLK1 inhibitors have been established. To this end, we conducted a post-hoc biomarker analysis of tumor samples from non-small cell lung cancer (NSCLC) patients treated with the PLK1 inhibitor BI2536 in a phase II study. Methods: We analyzed formalin-fixed paraffin-embedded surplus tumor tissue from 47 study patients using immunohistochemistry (IHC) and DNA sequencing of KRAS, EGFR, BRAF, and PIK3CA. Results:KRAS-mutated patients showed numerically prolonged progression-free survival, but statistical significance was not established. Interestingly, when pathways rather than single genes were analyzed, a positive correlation between IHC staining of activated ERK (p-ERK) and mutated KRAS was detected, whereas KRAS mutation status was found to be negatively correlated with activated AKT (p-AKT). Conclusion: With this hypothesis-generating study in BI2531-treated patients, we could not establish a correlation between KRAS mutations and relevant clinical endpoints. Future clinical trials with concomitant systematic biosampling and comprehensive molecular analyses are required to identify biomarkers predictive for response to PLK1 inhibitors. |
Databáze: | OpenAIRE |
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