Abstract 2387: The oncogenic role and therapeutic potential of PTPN11 in melanoma

Abstract

Abstract 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), is frequently activated in melanoma. Although implicated as an oncogene in multiple cancer types, the oncogenic role of PTPN11 has not been established in melanoma. Recently, we preformed whole exome sequencing on tumors generated by a mouse model driven by loss of PTEN and CDKN2A (INK4A/ARF) and 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; as well as, PTPN11's effect on the RAS/RAF/MEK/ERK signaling pathway and its activation status in human melanoma. PTPN11 can be activated by receptor tyrosine kinases (RTKs) or by point mutations. 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), supporting frequent activation of PTPN11 in human melanoma even though the mutation rate is low (1~3%). PTPN11 knock-down suppressed ERK activation in NRAS mutant and BRAF/NRAS wild-type melanoma cells, but not in BRAF mutant cells. Moreover, we have shown that expression of active PTPN11E76K mutant drives soft-agar colony growth in vitro, tumor growth in nude mice, RAS/RAF/MEK/ERK activation, and resistance to MEK inhibition. Alternatively, knock-down of Ptpn11 reduces colony growth and ERK activation. We generated a tet-inducible, melanocyte-specific, PTPN11E76K 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. Doxycycline withdrawal and subsequent extinction of PTPN11E76K caused regression of established tumors, supporting the tumor maintenance role of PTPN11. Subsequently, tumor tissue from this model underwent phosphor-tyrosine proteomic analysis to identify downstream effectors of PTPN11's protein tyrosine phosphatase activity. The proteins identified in this analysis are currently being confirmed. 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 Suzanne Hill, Evan Roberts, Ellen Marin, Xue Wang, Jamie Teer, Jane Messina, Jerry Wu, Minjung Kim. The oncogenic role and therapeutic potential of PTPN11 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2387.