ORT475503_Suppl.Material.pdf (638.64 kB)
Supplementary Material for: Comprehensive Biomarker Analyses in Patients with Advanced or Metastatic Non-Small Cell Lung Cancer Prospectively Treated with the Polo-Like Kinase 1 Inhibitor BI2536
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posted on 2017-06-20, 06:22 authored by Breitenbuecher F., von Pawel J., Sebastian M., Kortsik C., Ting S., Kasper S., Wohlschläger J., Worm K., Morresi-Hauf A., Schad A., Westerwick D., Wehler B., Werner M., Munzert G., Gaschler-Markefski B., Schmid K.W., Schuler M.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.