Abstract A04: Cross-species oncogenomics approach identifies PTPN11 as an oncogene and potential therapeutic target in melanoma
Authors: Hill Kristen S. , Wang Xue , Roberts Evan R. , Marin Ellen M. , Teer Jamie K. , Kim Youngchul , Messina Jane , Wu Jie , Kim Minjung 
Published: May 2018

Abstract
Melanoma is a deadly disease carrying many genetic mutations. A major challenge to the development of effective targeted therapies in melanoma is the identification of true “driver” mutations among numerous “passenger” alterations. Several previous studies support using cross-species comparative oncogenomic approaches for cancer gene discovery. Specifically, it has been shown that mice and humans share several genetic events in the development of cancer and that these events that are conserved across different species may point to functionally important and evolutionary conserved alterations targeting “driver” genes. Recently, we analyzed melanoma genomes from a mouse model driven by the loss of PTEN and CDKN2A (INK4A/ARF), commonly observed alterations in human melanoma patients, by whole-exome sequencing. This study identified several conserved cross-species orthologous mutations in Kras, Erbb3, and Ptpn11. In this study, we addressed the functional roles of PTPN11 in melanoma tumorigenesis and tumor maintenance, its effect on RAS/RAF/MEK/ERK signaling pathway, and its activation status in human melanoma.
Melanoma displays frequent activation of the RAS/RAF/MEK/ERK signaling pathway, which is intricately regulated by multiple proteins including PTPN11 (Tyrosine-Protein Phosphatase Non-Receptor Type 11, encoding SHP2). Although implicated as an oncogene in multiple cancer types, the oncogenic role of PTPN11 has not been fully established in melanoma. PTPN11 can be activated by receptor tyrosine kinases (RTKs) and/or by point mutations. Although the mutation rate is low (1~3%), we observed activating phosphorylation on Tyr 542 of PTPN11 in 40% (n=15/38) of melanoma specimens and the majority of human melanoma cell lines (n=14), indicating the potential frequent activation of PTPN11 in human melanoma. PTPN11 knock-down suppressed ERK activation in NRAS mutant (WM1361A, 1366, 1346) and BRAF/NRAS wt (WM3211, MeWo, CHL1) melanoma cells, but not in BRAF mutant (1205Lu, IGR1, 983C) cells. Moreover, we have shown that the expression of active PTPN11 E76K mutant drives soft-agar colony growth in vitro, tumor growth in nude mice, RAS/RAF/MEK/ERK activation, and resistance to MEK inhibition, whereas knock-down of Ptpn11 reduces colony growth and ERK activation. We generated a tet-inducible, melanocyte-specific, PTPN11 E76K transgenic mouse model in a Pten and Cdkn2a null background and observed melanoma formation. Implantation of melanoma cells derived from this model showed doxycycline-dependent tumor growth in nude mice; additionally, withdrawal of doxycycline and subsequent extinction of PTPN11 E76K caused regression of established tumors, supporting a tumor-maintenance role of PTPN11. These data support the oncogenic roles of PTPN11 in melanoma by regulating RAS/RAF/MAPK pathway activation and the value of PTPN11 as a novel and actionable therapeutic target.
Citation Format: Kristen S. Hill, Xue Wang, Evan R. Roberts, Ellen M. Marin, Jamie K. Teer, Youngchul Kim, Jane Messina, Jie Wu, Minjung Kim. Cross-species oncogenomics approach identifies PTPN11 as an oncogene and potential therapeutic target in melanoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A04.