Deficiency of PTPRH in pediatric solid tumors identifies a high-risk phenotype that can be overcome by combinatorial tyrosine kinase inhibition

Abstract As there is a paucity of targetable oncogenic drivers in pediatric solid tumors, we hypothesized that deficiency of select protein tyrosine phosphatases may allow proliferative signals to proceed unchecked in these cancers and that understanding these regulatory networks could inform therapy. In support of this possibility, the protein tyrosine phosphatase PTPRH has been previously reported to have a tumor-suppressive role in colon cancer and hepatocellular cancer. In the current study, we examine the role of PTPRH in pediatric solid tumors. Using multiple publicly available databases, we observed that low PTPRH expression is associated with significantly shorter survival in both neuroblastoma and osteosarcoma. Further, restoration of PTPRH expression in PTPRH-deficient neuroblastoma cells inhibits colony formation. In addition, we used a variety of biochemical approaches to identify novel PTPRH-binding partners and potential substrates. Moreover, we utilized these data to design combinatorial tyrosine kinase inhibitor therapies that target the cadre of receptor tyrosine kinases that are regulated by PTPRH. In particular, the combination of crizotinib and pazopanib inhibits proliferation of PTPRH-deficient neuroblastoma cells in vitro and reduces tumor growth in vivo. We are continuing to optimize the selection of tyrosine kinase inhibitors in order to most closely phenocopy restoration of PTPRH and maximize antitumor activity. Thus, we have shown that even for tumors that lack amplification or driver mutations of receptor tyrosine kinases, combinatorial tyrosine kinase inhibition can have substantial therapeutic activity and should be investigated further in the laboratory and the clinic. Citation Format: Kathleen A. Scorsone, Siddhartha Tyagi, Mayra C. Orellana, Sonal Gahlawat, Amritha Nair, Tingting Sun, Thomas F. Westbrook, Ronald J. Bernardi. Deficiency of PTPRH in pediatric solid tumors identifies a high-risk phenotype that can be overcome by combinatorial tyrosine kinase inhibition [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A43.