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MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model

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MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model Published OnlineFirst December 5, 2011; DOI: 10.1158/1535-7163.MCT-11-0400 Molecular Cancer Preclinical Development Therapeutics MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model Chandra Bartholomeusz1,2, Tetsuro Oishi1,2,6, Hitomi Saso1,2, Ugur Akar1,2, Ping Liu3, Kimie Kondo1,2, Anna Kazansky1,2, Savitri Krishnamurthy4, Jangsoon Lee1,2, Francisco J. Esteva1,2, Junzo Kigawa6, and Naoto T. Ueno1,2,5 Abstract Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is extracellular signal–related kinase (ERK). PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR–ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of 4 CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Furthermore, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to selumetinib sensitivity. Both selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model. However, selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss and severe skin peeling) at high doses. Our findings indicate that the MEK–ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that selumetinib and erlotinib are worth exploring as therapeutic agents for CCC. Mol Cancer Ther; 11(2); 360–9. Ó2011 AACR. Introduction patients with ovarian CCC and serous adenocarcinoma, the most common subtype of epithelial ovarian cancer, Clear cell carcinoma (CCC) of the ovary is responsible patients with stage III CCC had significantly lower 3- and for 3.7% to 12.1% of epithelial ovarian cancers (1, 2). The 5-year survival rates than patients with stage III serous clinical behavior of CCC of the ovary is distinctly different adenocarcinoma (23.5% vs. 54.1%, 23.5% vs. 34.1%). In from that of other epithelial ovarian cancers (3). In the first addition, response rates for platinum-based chemother- large study to examine survival and treatment response in apy were 11.1% for CCC and 72.5% for serous adenocar- cinoma (4). Authors' Affiliations: 1Breast Cancer Translational Research Laboratory, The epidermal growth factor receptor (EGFR) is fre- Departments of 2Breast Medical Oncology, 3Biostatistics, 4Pathology, and quently expressed in malignant ovarian tumors (48% of 5 Stem Cell Transplantation and Cellular Therapy, University of Texas MD tumors on average in the studies reported to date; ref. 5), Anderson Cancer Center, Houston, Texas; and 6Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan and in a phase II trial for advanced ovarian carcinoma, an EGFR tyrosine kinase inhibitor (TKI), erlotinib, showed Note: C. Bartholomeusz and T. Oishi contributed equally to this work. marginal activity (partial response, 6%; stable disease, Corresponding Authors: Naoto T. Ueno, Department of Breast Medical Oncology, Unit 1354, University of Texas MD Anderson Cancer Center, 44%; and progressive disease, 50%) but was generally 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-6168; well tolerated (6). All patients in that study had EGFR- Fax: 713-794-4385; E-mail: [email protected]; and Chandra positive disease by immunohistochemical analysis, but Bartholomeusz, Department of Breast Medical Oncology, Unit 1354, Uni- versity of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, there was no information with regard to the histologic Houston, TX 77030. Phone: 713-745-1086; Fax: 713-745-9296; E-mail: subtype. Therefore, the sensitivity of CCC to erlotinib is [email protected] not known. doi: 10.1158/1535-7163.MCT-11-0400 A major downstream target of the EGFR signaling Ó2011 American Association for Cancer Research. cascade is extracellular signal–related kinase (ERK). 360 Mol Cancer Ther; 11(2) February 2012 Downloaded from mct.aacrjournals.org on September 28, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst December 5, 2011; DOI: 10.1158/1535-7163.MCT-11-0400 Selumetinib Inhibits Growth of Ovarian Clear Cell Carcinoma Erlotinib inhibits the activation of the ERK pathway in KOC-7c, SMOV-2, and OVTOKO cells were maintained in several human non–small cell lung cancer cell lines (7). RPMI-1640 medium (GIBCO). Inhibition of ERK by EGFR-TKIs intercepts ERK’s upstream aberrant mitogenic signals. To date, no thera- Plasmid constructs peutically useful direct ERK inhibitors have been adopted The plasmid construct PEA-15-AA, the nonphosphory- in clinical practice. MEK1/2 plays a central role in inte- lated variant of PEA-15 (S104A/S116A), was a gift from gration of mitogenic signals into the ERK pathway, as Dr. Mark Ginsberg (University of California, San Diego, MEK has no downstream substrates except for ERK1/2. CA; ref. 13). To construct PEA-15-AD, we exchanged Thus, MEK is an excellent alternative therapeutic target serine 104 (Ser-104) for Ala. pcDNA3-PEA-15-S116D with which to modulate ERK activity. The MEK inhibitor served as a template using the primer 50-CAAGCT- PD-0325901 selectively binds to and inhibits MEK, which AACCCGTATCCCCGCTGCCAAGAAGTACAAAGA- results in inhibition of ERK phosphorylation and inhibi- C-30 and its reverse complement GTCTTTGTACTTC tion of tumor cell proliferation. However, PD-0325901 has TTGGCAGCGGGGATACGGGTTAGCTTG. been discontinued from Pfizer’s drug development pipe- line because the phase II trial of PD-0325901 showed no Drugs objective tumor response (8, 9). However, selumetinib Erlotinib was purchased from ChemieTek. Selumetinib (AZD6244), a potent, selective, ATP-uncompetitive inhib- was provided by AstraZeneca under the auspices of the itor of MEK1/2 kinases (10, 11), is currently in phase II National Cancer Institute’s Cancer Therapy Evaluation clinical trial development for melanoma and non–small Program. cell lung cancer. PEA-15 is a phosphoprotein that slows cell prolifer- Western blot analysis ation by binding to and sequestering ERK in the cyto- Cell pellets were lysed as described previously (16). plasm (12). The structure of PEA-15 indicates that phos- Primary antibodies were rabbit anti-EGFR antibody phorylation could regulate PEA-15 binding to ERK (13). (diluted 1:500; Santa Cruz Biotechnology), rabbit anti- We previously showed that transfection of low PEA-15– phospho-EGFR (Tyr1173; 1:200; Santa Cruz Biotechno- expressing ovarian cancer cells with PEA-15 inhibited logy), rabbit anti-phospho-p42/44 MAP kinase (Thr202/ cell proliferation (14). Analysis of PEA-15 expression in Tyr204; 1:500; Cell Signalling), rabbit anti-PEA-15 poly- a tissue microarray of epithelial ovarian cancer samples clonal antibody (1:1000; SynPep), rabbit anti-pPEA-15 revealed that PEA-15 expression is associated with (S104; 1:500; Cell Signalling), rabbit anti-pPEA-15 (S116; prolonged overall survival in patients with epithelial 1:500; Invitrogen), mouse anti-a-tubulin (1:5,000; Sigma- ovarian cancer (15). Aldrich), and mouse anti-b-actin (1:2,000; Sigma-Aldrich). We hypothesized that inhibition of the EGFR–ERK Signals were detected using an Odyssey IR imaging sys- pathway suppresses tumorigenicity in ovarian CCC. To tem (LI-COR Biosciences). evaluate this hypothesis, we tested the impact of erlotinib and selumetinib on cell proliferation. We found that WST-1 assay erlotinib suppressed cell proliferation in EGFR-overex- Cell viability was assayed using cell proliferation reagent pressing CCC cells, partly because of suppression of ERK. WST-1 (Roche Applied Science) as described previously Furthermore, erlotinib-sensitive cells were also sensitive (17). Ovarian CCC cells (RMG-I, 4 Â 103/90 mL; SMOV-2, to selumetinib. This selumetinib sensitivity of CCC cells 3 Â 103/90 mL; OVTOKO, 2 Â 103/90 mL; or KOC-7c, 2 Â was partially dependent on the phosphorylation status 103/90 mL) were seeded into each well of a 96-well plate and of PEA-15. Erlotinib and selumetinib suppressed CCC treated the next day with erlotinib or selumetinib at a final tumor growth in a mouse intraperitoneal xenograft mod- concentration of 0.001, 0.01, 0.1, 1, or 10 mmol/L for 72 hours. el. Our findings indicate that the MEK/ERK pathway may be a promising therapeutic target in EGFR-overexpres- Short interfering RNA against EGFR sing CCC. Cells were seeded in 6-well culture plates at 3.0 Â 105 cells/well (30%–50% confluence). The next day, cells were Materials and Methods transfected with ON-TARGET SMART pools against EGFR or a scrambled control (Dharmacon) at a final short Cell lines and cell cultures interfering RNA (siRNA) concentration of 100 nmol/L Four human ovarian CCC cell lines (RMG-I, KOC-7c, using DharmaFECT 1 (Dharmacon) following the manu- SMOV-2, and OVTOKO) were used. RMG-I was obtained facturer’s protocol. from Professor Shiro Nozawa, Keio University, Tokyo, Japan; KOC-7c from Dr. Toru Sugiyama, Kurume Uni- Cell-cycle distribution analysis versity, Japan; SMOV-2 from Dr. Tomohiro Iida, St. Mar- Briefly, cells were plated in a 6-well plate, cultured ianna University, Kawasaki, Japan; and OVTOKO from overnight,andthentreatedoruntreatedwitherlotinibfor Dr. Hiroshi Minaguchi, Yokohama City University, 48 hours (final concentration 0.1 or 1 mmol/L for RMG-I; Japan.
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