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The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity Daniel A.R

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The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity Daniel A.R Published OnlineFirst October 22, 2018; DOI: 10.1158/1078-0432.CCR-18-0277 Cancer Therapy: Preclinical Clinical Cancer Research The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity Daniel A.R. Heisey1, Timothy L. Lochmann1, Konstantinos V. Floros1, Colin M. Coon1, Krista M. Powell1, Sheeba Jacob1, Marissa L. Calbert1, Maninderjit S. Ghotra1, Giovanna T. Stein2, Yuki Kato Maves3, Steven C. Smith4, Cyril H. Benes2, Joel D. Leverson5, Andrew J. Souers5, Sosipatros A. Boikos6, and Anthony C. Faber1 Abstract Purpose: It was recently demonstrated that the EWSR1-FLI1 revealed increased expression of the antiapoptotic protein t(11;22)(q24;12) translocation contributes to the hypersensi- BCL-2 in the chemotherapy-resistant cells, conferring apo- tivity of Ewing sarcoma to PARP inhibitors, prompting clinical ptotic resistance to olaparib. Resistance to olaparib was evaluation of olaparib in a cohort of heavily pretreated Ewing maintained in this chemotherapy-resistant model in vivo, sarcoma tumors. Unfortunately, olaparib activity was disap- whereas the addition of the BCL-2/XL inhibitor navitoclax pointing, suggesting an underappreciated resistance mecha- led to tumor growth inhibition. In 2 PDXs, olaparib and nism to PARP inhibition in patients with Ewing sarcoma. We navitoclax were minimally effective as monotherapy, yet sought to elucidate the resistance factors to PARP inhibitor induced dramatic tumor growth inhibition when dosed in therapy in Ewing sarcoma and identify a rational drug com- combination. We found that EWS-FLI1 increases BCL-2 bination capable of rescuing PARP inhibitor activity. expression; however, inhibition of BCL-2 alone by veneto- Experimental Design: We employed a pair of cell lines clax is insufficient to sensitize Ewing sarcoma cells to ola- derived from the same patient with Ewing sarcoma prior to parib, revealing a dual necessity for BCL-2 and BCL-XL in and following chemotherapy, a panel of Ewing sarcoma cell Ewing sarcoma survival. lines, and several patient-derived xenograft (PDX) and cell line Conclusions: These data reveal BCL-2 and BCL-XL act xenograft models. together to drive olaparib resistance in Ewing sarcoma and Results: We found olaparib sensitivity was diminished reveal a novel, rational combination therapy that may be put following chemotherapy. The matched cell line pair forward for clinical trial testing. Introduction survival rate for patients with Ewing sarcoma presenting with metastasis or that relapse following systematic chemotherapy (1). The Ewing family of tumors (EWFTs), consisting of primitive The EWSR1-FLI1 t(11;22)(q24;q12) translocation event is neuroectodermal tumor (PNET) and Ewing sarcoma, is a malig- found in approximately 90% of EWFTs. Since the identification nancy of predominantly bone. These cancers are diagnosed most of EWSR1-FLI1 in Ewing sarcoma, it has become clear that the often in children and adolescents. Great strides have been made in resultant fusion oncogene is the vital driving event in these tumors treating localized disease by using intensive neoadjuvant and (2–7). The molecular consequence of juxtaposing the EWSR1 and adjuvant chemotherapy regimens, increasing the 5-year survival FLI1 genes is a EWS-FLI1 fusion protein where EWS potently from about 10% to approximately 75%. However, there is a 30% increases the ability of transcription factor FLI1 to activate or suppress target genes. Unfortunately, FLI1 is currently undruggable, and effective 1VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia. 2Massachusetts General Hospital Cancer Center, Boston, Massachu- targeted therapies for treating Ewing sarcoma remain elusive. fi setts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. Recent ndings have highlighted the role of EWS-FLI1 at inducing 3Crown Bioscience Inc., San Diego, California. 4Division of Anatomic Pathology, a wide range of changes throughout the epigenome, affecting both Virginia Commonwealth University, Richmond, Virginia. 5AbbVie, North Chi- histone marks and enhancers (5–9), leading to simultaneous 6 cago, Illinois. Hematology, Oncology and Palliative Care, School of Medicine enhanced expression of tumor oncogenes and reduced expression and Massey Cancer Center, Virginia Commonwealth University, Richmond, of tumor suppressors (6). However, these studies have yet to Virginia. reveal specific, druggable targets with associated clinically avail- Note: Supplementary data for this article are available at Clinical Cancer able therapies. Research Online (http://clincancerres.aacrjournals.org/). Brenner and colleagues (10) and the Genomics of Drug Sen- Corresponding Author: Anthony C. Faber, Virginia Commonwealth University, sitivity in Cancer (GDSC), a high-throughput drug screening Perkinson Building, Room 4134, 1101 East Leigh Street, Richmond, VA 23298. platform (11), both demonstrated in 2012 that EWSR1-FLI1– Phone: 804-828-0841; Fax: 804-828-0150; E-mail: [email protected] translocated Ewing sarcoma displays hypersensitivity to PARP doi: 10.1158/1078-0432.CCR-18-0277 inhibition; this has since been replicated by several other Ó2018 American Association for Cancer Research. groups (12–14). These data have provided a promising www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 22, 2018; DOI: 10.1158/1078-0432.CCR-18-0277 Heisey et al. Antibodies and reagents Translational Relevance Primary antibodies used for Western blotting were as follows: Using matched patient samples prior to and following GAPDH (sc-3233) and FLI1 (sc-365294) from Santa Cruz Bio- chemotherapy, we have uncovered a drug combination that technology; cleaved PARP1 (5625), BCL-2 (4223), BCL-XL is able to achieve substantial tumor regression in multiple (2764), MCL-1 (5453), PARP1 (9532), gH2A.X (9781), and mouse models including patient-derived xenografts and BIM (2933) from Cell Signaling Technology. Secondary anti- xenografts of chemotherapy-resistant cells. This warrants the bodies used were mouse IgG (GE Healthcare Life Sciences; clinical evaluation of olaparib in combination with navitoclax NXA931) and rabbit IgG (GE Healthcare Life Sciences; NA934). in the EWS-FLI1–translocated Ewing family of tumors. IgG (sc-2027) for immunoprecipitation was from Santa Cruz Biotechnology. Olaparib (AZD-2281) was from Abmole, and A-1331852, navitoclax (ABT-263), and venetoclax (ABT-199) were kindly provided by AbbVie Inc. drug target for EWFTs, with corresponding FDA-approved PARP1 inhibitors (15). Animal experiments  6 However, in the initial clinical study of olaparib in Ewing For the SK-ES-1 xenograft model, 5 10 cells were injected s.c. fl sarcoma, no objective responses were observed in 12 evalu- into the ank of 6- to 8-week-old Nu/Nu mice. For the CHLA10  6 fl able patients (15). Although there were no objective xenograft model, 5 10 cells were injected s.c. into the ank of responses, 4 of 12 patients achieved stable disease, with 2 6- to 8-week-old Nod/SCID gamma (NSG) mice. The patient- of the 4 achieving minor responses (tumor shrinkage of 9% derived xenograft (PDX) models were obtained from Crown  5 fl and 12%), indicating a modest level of efficacy by PARP Bioscience, and 5 10 cells were injected into the ank of NSG mice s.c. Treatment began when tumors reached approximately inhibition in these patients. 3 Based on the hypersensitivity of Ewing sarcoma to PARP 150 to 200 mm , and mice were randomized into treatment inhibition in vitro and olaparib activity in patients with Ewing cohorts. Tumor size and mouse weight were measured 3 days sarcoma, we sought to identify intrinsic resistance mechanisms per week with a digital scale and calipers, where tumor volume  2  to PARP inhibitor (PARPi) therapy as well as a rational drug was calculated as length width 0.52. Navitoclax and olaparib combination that could overcome these mechanisms. We and were administered by oral gavage. Navitoclax was dissolved in fi others have shown that a low apoptotic response, even in the 60% Phosal 50 PG, 30% PEG400, and 10% ethanol, for a nal presence of growth arrest, mitigates response to targeted therapies dosage of 80 mg/kg of body weight. Olaparib was dissolved fi (16–21). We therefore hypothesized that mitigated responses of in 10% hydroxylpropyl-b-cyclodextrin for a nal dosage of PARP inhibition may be due to loss of apoptotic potential of 100 mg/kg of body weight. All drugs were administered once per EWFTs, which could prove particularly true in the chemorefrac- day, 5 days/week. For pharmacodynamics studies, tumor-bearing tory population. This hypothesis was further supported by the fact mice were treated with drug for 3 days, and tumors were harvested fi that deficient DNA damage repair is thought to contribute to, if on the 3rd day 2 hours after the nal treatment. Tumors were fl not define, PARPi sensitivity in Ewing sarcoma (12), as well as the ashfrozeninliquidnitrogen.Forthebloodtoxicitystudy, established role of antiapoptotic BCL-2 family proteins in pro- NSG mice were treated with no drug (no Rx), navitoclax, tecting cancer cells from DNA damage–induced apoptosis olaparib, or the combination, at the same doses as above. At (17, 22) and their inverse correlation of expression to cytotoxic 3 and 7 days, mice were exsanguinated, and blood was sent to agent sensitivity (23). IDEXX BioResearch for testing. The recovery cohort was treated for 7 days and allowed 24 hours of recovery from treatment before exsanguination. All animal experiments were approved Materials and Methods by the Virginia Commonwealth University Institutional Animal Cell lines Care and Use Committee (IACUC protocol #AD10001048). A673 (ATCC CRL-1598) and HEK293T cells were cultured in DMEM (Gibco) with 10% FBS (Seradigm) and 1 mg/mL pen- Dataset analysis icillin and streptomycin. CHLA9 and CHLA10 cells were grown The online database for publically accessible drug sensitivity in DMEM with 20% FBS, 1 mg/mL penicillin and streptomycin, data (www.cancerRxgene.org) was used to generate Fig. 3C. The and 1% Insulin-Transferrin-Selenium 100x (Gibco). SK-ES-1 cancer cell line encyclopedia (CCLE; ref.
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