Abstract A088: SLC39A6-targeted combination therapy to reverse CAF-induced resistance in HER2+ breast cancer using a microfluidic platform

Abstract

HER2+ breast cancer accounts for 15–20% of invasive breast cancers, and although eight FDA-approved agents, including monoclonal antibodies, tyrosine-kinase inhibitors, and antibody-drug conjugates, have substantially improved patient survival, resistance in the advanced disease setting remains a significant unmet clinical need. Building on our prior preclinical work establishing fibroblasts as drivers of HER2 therapy resistance (Zervantonakis et al., PNAS 2020; Poskus et al., Cell Mol Bioeng 2024), we investigated transcriptional programs driven by cancer-associated fibroblasts (CAF) in patient tumors and patient-derived organoids to uncover new therapeutic targets in HER2+ breast cancer. First, we performed transcriptomic analysis of the NOAH clinical trial dataset and found that SLC39A6 (LIV-1/ZIP6) expression is significantly elevated in patients with residual disease compared to patients with pathologic complete response following HER2-targeted therapy. Importantly, high SLC39A6 expression is also associated with poor patient survival. Using a panel of HER2+ breast cancer cell lines and patient-derived organoids (PDOs), we found that SLC39A6 protein levels were significantly upregulated under CAF co-culture conditions in 4 out of 6 HER2+ breast cancer tumor models but not under monoculture conditions, establishing SLC39A6 as a candidate CAF-induced resistance mediator. To examine the role of SLC39A6 in mediating HER2-therapy resistance, HER2+ PDOs co-cultured with CAFs in 3D matrices were treated with Ladiratuzumab vedotin, an anti-SLC39A6 antibody-drug conjugate (ADC), in combination with lapatinib. The combination induced tumor cell growth suppression in CAF-protected PDOs more effectively than lapatinib, identifying a new strategy to overcome CAF-mediated resistance to HER2-targeted therapy. To dissect CAF-tumor cell interactions with spatial precision, we developed a novel 3D microfluidic co-culture platform that allows patterning of HER2+ PDOs and CAFs in hydrogel matrices and enables real-time, high-resolution imaging to monitor cancer cell growth, death, and CAF-PDO interaction dynamics. The proposed platform recapitulates CAF-rich and CAF-low tumor microenvironments and allows dissection of paracrine vs. contact-dependent CAF signaling by spatially separating CAFs and PDOs in distinct matrix regions. We demonstrated that under homogeneous patterning drug response results mirror those in macroscale 3D co-culture assays, presenting a physiologically relevant platform to study patient-specific CAF-tumor cell interactions and evaluate therapeutic strategies in a controlled 3D microenvironment. These findings identify SLC39A6 as a novel, actionable therapeutic target in CAF-rich HER2+ breast cancer and provide preclinical rationale for SLC39A6-directed ADC combination strategies. Our microfluidic PDO platform establishes a new paradigm for patient-specific drug screening in the context of the stromal tumor microenvironment. Zeina Habli, Tiangyang Li, Mathew Poskus, Ioannis Zervantonakis. SLC39A6-targeted combination therapy to reverse CAF-induced resistance in HER2+ breast cancer using a microfluidic platform [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A088.