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Targeting Hippo-Dependent and Hippo-Independent YAP1 Signaling for the 2 Treatment of Childhood Rhabdomyosarcoma 3

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Targeting Hippo-Dependent and Hippo-Independent YAP1 Signaling for the 2 Treatment of Childhood Rhabdomyosarcoma 3 Author Manuscript Published OnlineFirst on April 30, 2020; DOI: 10.1158/0008-5472.CAN-19-3853 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Targeting Hippo-dependent and Hippo-independent YAP1 signaling for the 2 treatment of childhood rhabdomyosarcoma 3 4 Katherine K. Slemmons1, Choh Yeung2, Joshua T. Baumgart2, Jhazeel O. Martinez Juarez1, 5 Amy McCalla2, Lee J. Helman1,3 6 7 8 1Department of Hematology/Oncology, Children’s Hospital Los Angeles, Los Angeles, 9 California; 2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 10 Bethesda, MD; 3Departments of Pediatrics and Medicine, University of Southern California, Los 11 Angeles, California 12 13 14 15 16 17 18 ___________________________________ 19 Running title 20 Targeting YAP1 signaling in RMS 21 Key words 22 Rhabdomyosarcoma, YAP1, YES1, DNA methyltransferase inhibitors 23 Corresponding author 24 Lee J. Helman, (323) 361-6058 25 Reprint requests 26 Send reprint requests to Lee J. Helman, 4650 Sunset Blvd MS#57, Los Angeles, CA 90027; 27 [email protected] 28 Disclosure of Potential Conflicts of Interest 29 L.J. Helman is a consultant for Boehringer Ingelheim, Roche Bioscience, SpringWorks, and VujaDe, 30 holds stock in AstraZeneca and Viela Bio, and has cooperative research and development 31 agreements with Boehringer Ingelheim and AbbVie. No potential conflicts of interest were disclosed 32 by the other authors. 33 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 30, 2020; DOI: 10.1158/0008-5472.CAN-19-3853 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma, yet 3 patients with metastatic or recurrent disease continue to do poorly, indicating a need for new 4 treatments. The SRC family tyrosine kinase YES1 is upregulated in RMS and is necessary for 5 growth, but clinical trials using single agent Dasatinib, a SRC family kinase inhibitor, have failed 6 in sarcomas. YAP1 (YES-associated protein) is highly expressed in RMS, driving growth and 7 survival when the upstream Hippo tumor suppressor pathway is silenced, but efforts to 8 pharmacologically inhibit YAP1 have been unsuccessful. Here we demonstrate that treatment of 9 RMS with DNA methyltransferase inhibitor (DNMTi) upregulates Hippo-activators RASSF1 and 10 RASSF5 by promoter demethylation, activating canonical Hippo signaling and increasing 11 inactivation of YAP1 by phosphorylation. Treatment with DNMTi decreased RMS cell growth 12 and increased apoptosis and differentiation, an effect partially rescued by expression of 13 constitutively active YAP (S127A), suggesting the effects of DNMTi treatment are in part due to 14 Hippo-dependent inhibition of YAP1. Additionally YES1 and YAP1 interacted in the nucleus of 15 RMS cells, and genetic or pharmacologic suppression of YES1 resulted in cytoplasmic retention 16 of YAP1 and decreased YAP1 target gene expression, suggesting YES1 regulates YAP1 in a 17 Hippo-independent manner. Combined treatment with DNMTi and Dasatinib targeted both 18 Hippo-dependent and Hippo-independent regulation of YAP1, ablating RMS cell growth in vitro 19 and trending towards decreased tumor growth in vivo. These results show that the mechanisms 20 regulating YAP1 in RMS can be inhibited by combinatorial therapy of DNMTi and Dasatinib, 21 laying the groundwork for future clinical investigations. 22 23 Significance 24 This study elucidates the signaling pathways that regulate the oncogenic protein YAP1 and 25 identifies a combination therapy to target these pathways in the childhood tumor 26 rhabdomyosarcoma. 2 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 30, 2020; DOI: 10.1158/0008-5472.CAN-19-3853 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Introduction 2 Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. While 3 outcomes for patients with localized disease have improved, patients with metastatic or recurrent 4 disease continue to do poorly, therefore new treatments are needed (1,2). The two most common 5 subtypes of RMS, embryonal (eRMS) and alveolar (aRMS), are phenotypically and molecularly 6 distinct but often treated with the same modalities. Standard of care treatment includes a 7 combination of surgery, radiation, and a backbone of cytotoxic chemotherapies made up of 8 vincristine, actinomycin D, and cyclophosphamide but does not include any targeted therapies. 9 eRMS is characterized by genomic instability with high rates of copy number alternations, single 10 nucleotide variations and up to one third have alterations in the RAS signaling pathway (3,4). On 11 the other hand, aRMS is characterized by a distinct PAX3/7-FOXO1 (PF) chromosomal 12 translation creating a fusion transcription factor. PF expression results in widespread 13 transcriptional disruption and upregulation of oncogenic pathways including FGFR4 and IGF 14 signaling (5). The presence of the PF fusion gene portends a worse prognosis with a 5 year 15 survival rate of 52% for localized disease, and 19% when metastatic (6). 16 The YAP1 protein was initially discovered as the YES-associated-protein. YES1, a SRC 17 family tyrosine kinase (SFK), has been shown to be upregulated in RMS and drive tumor cell 18 proliferation (7). Although the YES1 kinase is targetable using Dasatinib and other kinase 19 inhibitors, to date it has not proven to be effective in clinical trials in RMS (8). However, the 20 relationship between YES1 and YAP1 in RMS has not been studied. 21 YAP1 was discovered to be the terminal oncoprotein in the Hippo tumor suppressor 22 pathway, a developmental pathway that regulates organ size and tissue regeneration. MST1/2, 23 the mammalian ortholog of Hippo, is a tumor suppressor that initiates a phosphorylation cascade 24 through LATS1/2 that results in the phosphorylation of YAP1 and its homolog TAZ at conserved 3 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 30, 2020; DOI: 10.1158/0008-5472.CAN-19-3853 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 serine residues. Once phosphorylated, YAP1 is sequestered in the cytoplasm and can be 2 degraded. MST1/2 is regulated upstream by many inputs including cell-to-cell contact, actin 3 cytoskeleton, and the RASSF family of scaffold proteins. When MST1/2 is inactive, YAP1 is not 4 phosphorylated and translocates to the nucleus where it functions as a transcriptional co- 5 activator, binds the TEAD family of transcription factors, and initiates transcription of pro-growth 6 and anti-apoptotic genes (9). Hippo signaling is dysregulated in many cancer types through 7 epigenetic silencing of Hippo-activator RASSF1, MST1/2 or LATS1/2, or through general 8 upregulation of YAP1 and/or TAZ expression. YAP1 is highly expressed in human RMS tumors 9 where it has been shown to promote proliferation, survival, and stemness, and inhibit myogenic 10 differentiation (10–12). While YAP1 is an ideal therapeutic target in cancer, a specific YAP1 11 inhibitor has yet to reach the clinic. We aimed to identify a clinically-relevant therapy to inhibit 12 YAP1 in RMS. 13 Here we demonstrate that treatment with a DNA methyltransferase inhibitor (DNMTi) can 14 inhibit YAP1 in a Hippo-dependent manner through alteration of RASSF family expression 15 (upstream MST1/2 regulators). Furthermore, YAP1 is regulated in a Hippo-independent manner 16 through YES1 and this regulation can be inhibited through treatment with a SRC family kinase 17 inhibitor, Dasatinib. Lastly, a combined treatment results in ablation of cell growth and induction 18 of apoptosis. These data suggest a potential therapeutic strategy using the combination of 19 DNMTis and SFK inhibitors for the treatment of recurrent/refractory RMS, particularly the alveolar 20 RMS subtye. 21 Materials and Methods 22 Generation of Cell Lines and Constructs 23 Human RMS cell lines RD (eRMS) and Rh30 (aRMS) were obtained from ATCC. Rh28 and 24 RMS559 were obtained from Dr. Javed Khan (NCI, Bethesda, MD). Rh36 eRMS cell line was 4 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 30, 2020; DOI: 10.1158/0008-5472.CAN-19-3853 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 obtained from Dr. Maria Tsokos (Beth Israel Medical Center, Boston, MA). Rh41 aRMS cell line 2 was obtained from Dr. Peter Houghton (St Jude's Children's Research Hospital, Memphis, TN). 3 Cell line authentication was performed in November 2018 using STR analysis (Promega 4 PowerPlex 16 HS System) conducted by the University of Arizona Genetics Core. The cell lines 5 were cultured in RPMI-1640, 100 units/ml penicillin and 100 μg/ml streptomycin, 2 mM glutamine, 6 and 10% heat inactivated fetal bovine serum at 37ºC in an atmosphere of 5% CO2. Lentivirus 7 shYES clones 9 and 11 were obtained from Sigma (TRCN0000001609 and TRCN0000001611, 8 respectively) and used as previously described (7). YAPS127A cell line was constructed by 9 transfecting Rh30 cells with pCDNA4/HismaxB-YAP1-S127A (Addgene plasmid # 18988) and 10 vector control cell was transfected with pCDNA4/TO (Thermo Fisher) using Nucleofector (Lonza) 11 program B032, buffer V, using 2x106 cells, and 2µg of plasmid. Cells were batch selected using 12 zeocin (Thermo Fisher). YEST348I cell line was constructed by stably expressing YES1 (T348I) 13 in pLX303 (Addgene plasmid # 42564) or vector control pLX304 (Addgene plasmid # 25890) in 14 Rh30 cells using established lentiviral methods (11). Cells were batch selected using blasticidin 15 (Invitrogen).
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