Abstract B29: SHANK3 in oncogenic RAS signaling

Abstract RAS proteins play a direct causal role in human cancers, with activating mutations in RAS occurring in ∼30% of tumors. Despite comprehensive efforts, efficient targeting of RAS has not yet reached the clinic. Here, we report SHANK3, a synaptic scaffolding protein and a regulator of integrin activity, as a novel tumor suppressor targeting RAS proto-oncogenes, especially mutant KRAS. We previously found the N-terminal part of SHANK3 as an unexpected RAS-association domain with high affinity for active RAS proteins. Now we show that the direct binding of SHANK3 to active RAS abrogates the MAPK/ERK signaling and thereby inhibits the RAS-stimulated transformation and slows the growth of RAS-dependent tumor cells. SHANK3 expression is downregulated in RAS-driven human cancers, and high expression of SHANK3 correlates with improved patient survival in KRAS-driven pancreatic and lung adenocarcinoma. These data support that targeting the MAPK/ERK pathway by SHANK3 represents a novel promising therapeutic approach for RAS-driven cancers. Citation Format: Johanna Lilja, Guillaume Jcaquement, Itziar Martinez D. Posada, Petra Laasola, Ella-Maria Vesilahti, Mitro Miihkinen, Siiri Salomaa, Hans-Juergen Kreienkamp, Igor Barsukov, Daniel Abankwa, Johanna Ivaska. SHANK3 in oncogenic RAS signaling [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B29.