Abstract 2834: CyclinE1 amplification promotes chromosomal instability and distinct vulnerabilities in gastroesophageal adenocarcinoma

Abstract Background: Gastroesophageal adenocarcinomas (GEA) are characterized by chromosomal instability (CIN) predominantly consisting of high amplitude focal amplifications of oncogenes, including Cyclin E1. An initial pan-cancer analysis revealed that CCNE1 is one of the top genes whose expression correlates with focal CIN. Objective: We proposed a causal role for excess CCNE1 as a driver of CIN and gastroesophageal tumorigenesis, and investigated the therapeutic vulnerabilities of CCNE1 amplification/overexpression. Design: We engineered a novel CCNE1-overexpressing mouse gastric organoid model with Trp53 deletion and studied the functional effects on tumor initiation and progression. Whole genome sequencing of tumors was performed to characterize the effects of CCNE1 overexpression on genomic instability. To identify dependencies of CCNE1-amplified GEA, we executed a CRISPRi functional genomic screen. Top genetic dependencies were translated into potential pharmacologic vulnerabilities and tested in monotherapy and combination. Results: CCNE1 overexpression accelerated tumor initiation and progression of mouse gastric organoids with Trp53 deletion. These tumors demonstrated increased chromosomal complexity, mainly focal amplifications. Our functional genomic screen identified specific genetic dependencies of CCNE1-amplified GEA, including CCNE1/CDK2 as the strongest hits, and SKP2 as a novel dependency likely through its function as a p27 degrader. Pharmacologic inhibition of CDK2 was insufficient and antagonistic with concurrent inhibition of the DNA damage response via targeting the ATR/CHEK1 axis. However, staggered inhibition of these distinct vulnerabilities demonstrated efficacy. Conclusions: Our study identifies CCNE1 as a driver of CIN in GEA and builds a foundation for further exploration of therapies for CCNE1-amplified GEA characterized by genomic instability. Citation Format: Zhong Wu, Ankur Nagaraja, Shangwei Sun, Ling Lan, Jin Zhou, Adam Bass. CyclinE1 amplification promotes chromosomal instability and distinct vulnerabilities in gastroesophageal adenocarcinoma [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 2834.