Abstract PO029: Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer

Abstract NRF2 is an “undruggable” oncogenic transcription factor recurrently mutated in solid tumors such as liver and lung cancers. Our recent study demonstrates that NRF2 acts by coordinating the redox and metabolic stress responses as well as drug resistance programs in liver and other cancers. Developing an NRF2 inhibitor is a major goal of cancer drug discovery. Here, we identify the non-canonical Hippo pathway protein serine/threonine kinase 38 (STK38/NDR1) as a new NRF2 kinase that is a requirement for its stability and function. STK38 directly phosphorylates NRF2 at two sites (S33 and T559), and both sites contribute to full NRF2 activation. Loss of STK38 disables the redox response in NRF2 driven cancers and leads to tumor regression in vivo. Conversely, STK38 can also activate NRF2 and promote de novo liver cancer development in mice. This oncogenic effect is reflected in low frequency (3%) genomic amplifications in human liver cancers. Importantly, inhibition of the upstream STK38-activating mammalian Hippo kinases STK3/4 (MST2/1) by XMU-MP-1 inactivates STK38-NRF2 regulatory axis in vitroand in vivo. More importantly, XMU-MP-1 produces single agent activity against NRF2-driven liver and lung cancers in vivo in primary and patient derived xenograft (PDX)-based mouse models. In addition, we performed an in-silicoscreen and identified TAE-684 as an STK38 inhibitor that was subsequently confirmed to block STK38 activity in an in vitro kinase assay. TAE-684 treatment resulted in significant growth impairment of NRF2-mutant PDXs in vivo but no activity was observed in NRF2 wildtype counterparts. Together, these results uncover a surprising role of Hippo-related kinase STK38 in NRF2 activation and point to a paradoxical vulnerability in NRF2-driven cancers. Citation Format: Viraj Sanghvi, Aleksander Rust, Josef Leibold, Scott Lowe, Agnes Viale, John Chodera, Ronald C. Hendrickson, Elisa de Stanchina, Hans-Guido Wendel. Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO029.