Abstract 4314: Understanding the mode of action and development of resistance towards HER2 targeting agents in preclinical in vivo models

Treatment options for HER2 positive cancer types have advanced significantly over recent years, focusing on targeted therapies that inhibit HER2 signaling and more recently using HER2 as the anchor-signal to bring tumor killing moieties or effector immune cells near the cancer cell. In our recent study we compared in vivo efficacy in tumor bearing immune-compromised mice using four different modalities in a proof-of-concept format in a HER2+ ovarian cancer xenograft model, SKOV-3. We then tested a panel of HER2 targeting agents in a broader range of clinically relevant PDX models of breast, ovarian and gastric cancer and correlated these results with different characteristics of the PDX models, such as HER2 expression (by IHC) and molecular phenotype (by WES and RNAseq). The range of modalities that were tested in this study comprised small molecules, antibodies, antibody-drug conjugates (ADC) and mRNA-LNP encoded antibodies. Antitumoral activity was measured as tumor growth inhibition (TGI) based on twice weekly tumor volume measurements. The sensitivity of SKOV-3 was heavily influenced by the modality of the respective drug. Whereas small molecule Lapatinib showed only mild efficacy (TGI 40%), Trastuzumab was moderately active (TGI 57%) compared to Trastuzumab-emtansine (TGI 68%). An mRNA-LNP encoding for trastuzumab was the most efficacious treatment with a TGI of 88%. Despite this, none of the treatments induced complete remission. The ongoing analysis of tumor tissue from these studies suggests an escape mechanism via epithelial-mesenchymal transition (EMT) as Vimentin is upregulated and E-Cadherin is downregulated in tumors after re-growth. The superior activity of the mRNA-encoded trastuzumab compared to the clinically approved therapeutic is likely to be due to the elevated and sustained trastuzumab protein levels in the serum of the tumor bearing animals. Broader screening across 33 PDX models revealed ADCs (trastuzumab-emtansin and trastuzumab-deruxtan) as the most efficacious modalities leading to higher TGI values with prolonged persistence of tumor remission. Two therapeutic antibodies (trastuzumab and pertuzumab) showed similar activity patterns despite their slightly different modes of action. HER2 expression correlated with the sensitivity of the PDX model, although this relationship was not strictly linear. HER2 has provided oncologists a tractable target for some cancer types. However, clinical as well as preclinical data indicate the further untapped potential of HER2 as a therapeutic target. Screening studies like those described are important tools to deconvolute sensitivity and possible mechanisms of resistance in a preclinical setting. This provides opportunities to discover biomarkers to better enable patient selection and to provide a better understanding of HER2 biology, further maximizing its therapeutic potential. Citation Format: Eva Oswald, Philipp Meyer, Loreen Weichert, Roxana Redis, Dan Rocca, Louise Brackenbury, Justin Bryans, Julia B. Schueler. Understanding the mode of action and development of resistance towards HER2 targeting agents in preclinical in vivo models [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 4314.