Targeting loss of the Hippo signaling pathway in NF2-deficient papillary kidney cancers

// Carole Sourbier 1, * , Pei-Jyun Liao 1, * , Christopher J. Ricketts 1 , Darmood Wei 1 , Youfeng Yang 1 , Sarah M. Baranes 1 , Benjamin K. Gibbs 1 , Lernik Ohanjanian 1 , L. Spencer Krane 1 , Bradley T. Scroggins 2 , J. Keith Killian 3 , Ming-Hui Wei 1 , Toshiki Kijima 1 , Paul S. Meltzer 3 , Deborah E. Citrin 2 , Len Neckers 1 , Cathy D. Vocke 1 and W. Marston Linehan 1 1 Urologic Oncology Branch, CCR, National Cancer Institute, NIH, Bethesda, MD, USA 2 Radiation Oncology Branch, CCR, National Cancer Institute, NIH, Bethesda, MD, USA 3 Genetics Branch, CCR, National Cancer Institute, NIH, Bethesda, MD, USA * These authors contributed equally to this work Correspondence to: W. Marston Linehan, email: wml@nih.gov Keywords: NF2; PRCC; hippo pathway; yes; dasatinib Received: September 07, 2017 Accepted: November 20, 2017 Published: January 10, 2018 ABSTRACT Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15–20% of all kidney neoplasms and may require diverse therapeutic approaches. Alteration of the NF2 tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC. The Hippo signaling pathway controls cell proliferation by regulating the transcriptional activity of Yes-Associated Protein, YAP1. Loss of NF2 results in aberrant YAP1 activation. The Src family kinase member Yes also regulates YAP1 transcriptional activity. This study investigated the importance of YAP and Yes activity in three NF2 -deficient PRCC cell lines. NF2 -deficency correlated with increased expression of YAP1 transcriptional targets and siRNA-based knockdown of YAP1 and Yes1 downregulated this pathway and dramatically reduced cell viability. Dasatinib and saracatinib have potent inhibitory effects on Yes and treatment with either resulted in downregulation of YAP1 transcription targets, reduced cell viability, and G0-G1 cell cycle arrest. Xenograft models for NF2 -deficient PRCC also demonstrated reduced tumor growth in response to dasatinib. Thus, inhibiting Yes and the subsequent transcriptional activity of YAP1 had a substantial anti-tumor cell effect both in vitro and in vivo and may provide a viable therapeutic approach for patients with NF2 -deficient PRCC.