Abstract A065: Lineage tracing oncogenic isoforms of HER2 in a mouse model of pancreatic cancer

Abstract

Abstract Among the numerous clinical challenges of pancreatic ductal adenocarcinoma (PDAC) is the eventual development of therapeutic resistance. Although previous studies report that only about 3% of PDAC cases are HER2 gene amplified, as many as 82% of PDAC tumors may have HER2 overexpressed. Anti-HER2 therapy with trastuzumab has yielded tremendous therapeutic success in breast cancer and multiple gastrointestinal malignancies, however minimal benefit is found in PDAC. Experimental mouse models have demonstrated initiation and acceleration of pancreatic tumorigenesis through overexpression of activated mutant HER2, yet the role of HER2 alone as a driver of PDAC and treatment resistance is still unknown. Multiple HER2 isoforms exist that are generated either via alternative splicing and loss of exon 16 (d16 HER2) or through N-terminal truncations (p95 HER2). These isoforms are implicated in differential responses to anti-HER2 therapy in the breast. Previously we described a HER2+ cancer rainbow mouse model in which human wild-type HER2 (WT HER2), d16 HER2, and p95 HER2 were expressed in the same mouse and lineage traced through co-expression of fluorescent protein reporters. Studies in the mammary gland revealed that each isoform drives distinct tumor phenotypes. Herein, we hypothesize that these isoforms drive HER2 positive PDAC. HER2 Crainbow mice were crossed with mice expressing PDX1-Cre recombinase to initiate recombination and expression of each fluorescently labelled HER2 isoform during pancreas development. PDX1-Cre/HER2 Crainbow (PHBOW) mice were followed for up to one year and sacrificed to lineage trace each isoform and register HER2 lineages with histopathology. Within our pilot cohort, early-stage pre-malignant pancreatic intraepithelial neoplasia (PanIN-1) was observed in 75% of PDAC HER2bow mice as early as five weeks. By one year, 50% demonstrated high grade PanIN (i.e. PanIN-3) and features of early invasion. Although WT HER2 was expressed abundantly throughout the pancreas, lineage tracing revealed WT HER2 was not found in pre-malignant lesions. Conversely, the pre-malignant PanIN lesions and early invasive histopathologic features traced to d16 HER2 expressing cells, while p95 HER2 traced with areas of acinar-to-ductal metaplasia, lesions known to be early initiators of pancreatic dysplasia. Our data show how the oncogenic HER2 isoforms, and not WT HER2, are able to drive PanIN lesions and, at lower frequency, invasive PDAC after one year. Future work seeks to complete HER2 Crainbow lineage tracing in PHBOW mice, test HER2 targeted therapy in PHBOW mice, and quantify HER2 isoforms in HER2+ human PDAC cases. Citation Format: Elishama N. Kanu, Joelle Sills, Rebecca Shelley, Joshua D. Ginzel, Joseph Fernandes, Ashley A. Fletcher, Peter J. Allen, Daniel P. Nussbaum, Joshua C. Snyder. Lineage tracing oncogenic isoforms of HER2 in a mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A065.