Abstract 3480: The HER2Δ16 splice variant fuels breast cancer metastasis through integrin-driven signaling

Abstract The HER2Δ16 splice variant, generated by exclusion of exon 16 from ERBB2, is frequently detected in aggressive HER2-positive breast tumors and has been linked to enhanced tumorigenicity and therapy resistance. Unlike full-length HER2, HER2Δ16 forms constitutively active homodimers, yet the mechanisms driving its aggressive behavior remain poorly defined. Using isogenic models expressing full-length HER2 or HER2Δ16, we integrated cell surface proteomics with transcriptomic profiling to identify pathways uniquely altered by the splice variant. HER2Δ16 expression induced a wide range of cell-surface changes, including a striking enrichment of RGD-binding integrins. This remodeling was validated in HER2-positive patient tumors stratified for high versus low HER2Δ16 expression. HER2Δ16 cells displayed robust activation of the focal adhesion kinase (FAK) pathway and exhibited enhanced migration, invasion, and anchorage-independent growth. Functional perturbation studies demonstrated that HER2Δ16-driven aggressiveness requires integrin signaling. Integrin depletion or pharmacological inhibition of FAK significantly impaired motility, invasion, and growth in soft agar. In vivo, systemic FAK inhibition markedly reduced HER2Δ16 tumor growth and metastatic dissemination in immunodeficient mice, establishing integrin-FAK signaling as a therapeutic vulnerability associated with HER2Δ16 expression. These findings identify integrin-FAK signaling as a central effector of HER2Δ16-induced metastasis and reveal a previously unrecognized mechanism by which this splice variant rewires the adhesion landscape to promote invasive progression. Targeting integrin-driven signaling may provide a promising strategy to counteract metastatic dissemination in HER2Δ16-positive breast cancer. Citation Format: Guillaume de Lhoneux, Jonathan Boucher, Geneviève Lavoie, Laure Voisin, Marc K. Saba-El-Leil, Sylvain Meloche, Philippe P. Roux. The HER2Δ16 splice variant fuels breast cancer metastasis through integrin-driven signaling abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3480.