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Volume 145, Issue 1, Pages 159-166 (April 2017) MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells Reto S. Kohler, Henriette Kettelhack, Alexandra M. Knipprath-Mészaros, André Fedier, Andreas Schoetzau, Francis Jacob, Viola Heinzelmann-Schwarz Gynecologic Oncology Volume 145, Issue 1, Pages 159-166 (April 2017) DOI: 10.1016/j.ygyno.2017.02.016 Copyright © 2017 The Authors Terms and Conditions

Fig. 1 MELK is elevated in various cancers and is a predictor disease-free survival in all TCGA cancer samples regardless of the cancer subtype. (A) Kaplan-Meier curve for disease-free survival for low and high MELK expression in all TCGA cancer samples. (B) Transcriptomic data set analysis. Box-whisker plots (data log transformed) showing MELK gene expression in the various cancers compared to “normal” kidney (ovarian cancer indicated by arrow). Gynecologic Oncology 2017 145, 159-166DOI: (10.1016/j.ygyno.2017.02.016) Copyright © 2017 The Authors Terms and Conditions

Fig. 2 MELK expression is associated with aggressive ovarian cancer subtypes. Bar chart showing MELK expression in the different subtypes as published in Heinzelmann et al. 2004 [10,11] (A). (B) Kaplan-Meier curve for low and high MELK expression (threshold determined by conditional inference trees) and progression-free survival (TCGA data set for high-grade SOC). Gynecologic Oncology 2017 145, 159-166DOI: (10.1016/j.ygyno.2017.02.016) Copyright © 2017 The Authors Terms and Conditions

Fig. 3 (A) Differential MELK expression in ovarian cancer cell lines as retrieved from the “Cancer Cell Line Encyclopedia (CCLE)” Broad Institute data base. Data are normalized and cell lines are sorted by descending MELK expression. MELK expression in MDA-MB-468 basal-like breast cancer cells (indicated in red) and T47D (blue) and MCF-7 (green) luminal breast cancer cells are shown as references. (B) Western blot displaying MELK expression in cell lines representing the ovarian surface epithelium, fallopian tube epithelium, and HGSOC. Whole cell protein extracts were produced, separated, and analyzed as described in “Materials and methods”. Tubulin is the sample loading control. Gynecologic Oncology 2017 145, 159-166DOI: (10.1016/j.ygyno.2017.02.016) Copyright © 2017 The Authors Terms and Conditions

Fig. 4 Effects of MELK depletion and pharmacological inhibition of MELK activity on cell cycle transition, morphology, colony formation, apoptosis, and proliferation. (A) Apoptosis induction (top panel) and oncogenic growth inhibition in soft-agar (bottom) in shRNA-mediated MELK-depleted cells. (B) OTSSP167 inhibits anchorage-independent growth in soft agar. (C) OTSSP167 reduces colony growth formation (anchorage-dependent). (D) Western blot for PARP1-cleavage in cell lines representing the ovarian surface epithelium (HOSE), the fallopian tube epithelium (FT), and ovarian cancer cell lines of various histotypes. Whole cell protein extracts of cell cultures treated with 100nM OTSSP167 for 48h were produced, separated, and analyzed. Tubulin, sample loading control; luminal (T47D) and basal (MDA-MB-468) breast cancer cell lines: negative and positive MELK controls, respectively. (E) MTT-assay results for the cell lines indicated presented as IC50 concentrations sorted by the histotypes (fallopian tubes, ovary surface epithelium, HGSOC). Cells were exposed to OTSSP1167 for 72h. Mean±SD of at least four independent experiments performed in quadruples. For further details, see “Material and methods”. Gynecologic Oncology 2017 145, 159-166DOI: (10.1016/j.ygyno.2017.02.016) Copyright © 2017 The Authors Terms and Conditions

Fig. 5 OTSSP167 and drug resistance. Sensitivity to OTSSP167 of Cisplatin-resistant TYK-nu(R) and -sensitive TYK-nu (A) and Paclitaxel-resistant IGROV1-PXL and -sensitive IGROV1 cells (B). (C) MDR1 expression (Western blot) in parental IGROV1 and TYK-nu cells and in their respective resistant counterparts (pxl5 and nu(R)). Tubulin is sample loading control and Pos is positive MDR1 control. (D) Sensitivity to OTSSP167 of OVCAR8 and OVCAR8-OTS cells (obtained by four cycles of step-wise exposure to increasing OTSSP167 concentrations: details in “Materials and methods”) and their cross-sensitivity to Carboplatin, Paclitaxel, and Doxorubicin. Effect of co-treatment of OVCAR8 cells with OTSSP167 and Carboplatin (E) or Paclitaxel (F) on cell viability: white bars (Carboplatin or Paclitaxel alone), grey bars (Carboplatin or Paclitaxel plus 50nM OTSSP167), black bars (Carboplatin or Paclitaxel plus 70nM OTSSP167). MTT-assay results presented as mean±SD of at least 3 independent experiments performed in quadruples. Gynecologic Oncology 2017 145, 159-166DOI: (10.1016/j.ygyno.2017.02.016) Copyright © 2017 The Authors Terms and Conditions