Abstract 4313: COPS5 inhibition synergizes the antitumor effect of trastuzumab by PTEN upregulation in HER2 amplified gastric cancer

Abstract COP9 Signalosome Subunit 5 (COPS5), a deubiquitinating enzyme, contributes to chemoresistance, and its expression is closely correlated with poor prognosis in patients with solid tumors. However, the role of COPS5 amplification in patients with gastric cancer (GC) and its inhibition in HER2-amplified GC models has never been elucidated. In the curated stomach adenocarcinoma cohort (n=294) from The Cancer Genome Atlas datasets, COPS5 amplification significantly co-occurred with HER2 amplification (10.5% vs. 2.7%, P=0.040) and was associated with worse disease-free survival (median 12.6 vs. 45.2 months, P=0.012) and overall survival (median 21.4 months vs. not reached, P=0.004) after surgery. In HER2-amplified GC cell lines, NCI-N87, SNU216, and OE19, COPS5 inhibition using CSN5i-3, a selective COPS5 inhibitor, synergistically enhanced the antiproliferative effect of trastuzumab. After CSN5i-3 treatment, COPS5 knock-out (KO) cell lines demonstrated a uniform increase in PTEN transcription and translation levels. This effect was mediated by SNAIL ubiquitination, suppressing the AKT downstream signaling pathway. However, in PTEN KO cell lines, the synergistic effect of CSN5i-3 and trastuzumab was not apparent. Similarly, reduced PTEN expression caused by SNAIL overexpression also decreased the responsiveness of CSN5i-3 treatment. Moreover, COPS5 KO cells exhibited increased sensitivity to the proliferative effect and downstream signaling inhibition of AKT inhibitors MK2206 and capivasertib compared to control cells. In a mouse xenograft model of NCI-N87 cells, CSN5i-3 treatment combined with trastuzumab yielded a synergistic anti-tumor effect compared to monotherapy without notable changes in body weight. This effect was accompanied by enhanced apoptosis and reduced SNAIL and AKT downstream signaling activity. In conclusion, the synergistic antiproliferative effect of COPS5 inhibition and trastuzumab was attributed to increased PTEN expression via SNAIL ubiquitination, resulting in the AKT downstream inhibition. These findings highlight the potential of COPS5 as a therapeutic target in combination with trastuzumab for HER2-amplified GC, warranting further clinical studies. Citation Format: Sung-Hyun Hwang, Ji-Won Kim, Kuijin Kim, Haseseong Park, Andrew Aguirre, Keun-Wook Lee. COPS5 inhibition synergizes the antitumor effect of trastuzumab by PTEN upregulation in HER2 amplified gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4313.