Abstract LB052: PTP1B inhibitors activate a novel hypoxia-induced inflammatory cell death pathway in breast cancer

Abstract

Abstract Dual PTP1B/TC-PTP (PTPN1/2) inhibitors are in clinical trials for multiple cancer types, primarily because they augment anti-tumor immunity, but they can also have cancer cell-autonomous effects. Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency/inhibition promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ~600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. We now report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. CYLD-deleted HER2+ cell-derived xenografts phencopy the effects of PTP1B deficiency, and reconstituting RNF213 knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning “cold” tumors “hot”, thereby increasing the potential clinical utility of PTP1B inhibitors. Citation Format: Benjamin G. Neel, Abhishek Bhardwaj, Maria Antonelli, Beatrix Ueberheide. PTP1B inhibitors activate a novel hypoxia-induced inflammatory cell death pathway in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB052.