Abstract 1917: HER2-FGFR1 interaction induced by bispecific molecules: A novel strategy for treating breast cancer

Abstract

Abstract Breast cancer poses a significant global health challenge, demanding effective therapies targeting specific receptors. In our prior study, we engineered molecules capable of binding to both HER2 and FGFR1, pivotal receptors in breast cancer progression. By combining the high-affinity Affibody ZHER2:2891 for HER2 with a modified, stable form of FGF2 binding to FGFR1, we created the bispecific protein (AfHER2-lFGF2). This innovative molecule could simultaneously recognize HER2 and FGFR1, exhibiting enhanced cell penetration. When coupled with the potent cytotoxic agent monomethyl auristatin E (MMAE), it demonstrated exceptional efficacy in eliminating cancer cells expressing HER2, FGFR, or both receptors. Our current investigation focused on quantifying the interaction between HER2 and FGFR1 receptors on the cell surface upon treatment with these bispecific molecules. Leveraging fully quantified spectral imaging FRET (FSI-FRET), a technique utilizing spectrally resolved two-photon microscopy. We directly monitor the association of HER2 and FGFR1 in the plasma membrane. Our findings revealed that the bispecific AfHER2-lFGF2 molecule forces interaction between HER2 and FGFR1 on the cell surface. Furthermore, we analyzed the activation of the HER2-FGFR1 complex and subsequent downstream signaling pathways using western blotting. In summary, our research uncovers the ability of the AfHER2-lFGF2 bispecific protein to foster direct interaction between HER2 and FGFR receptors on the cell membrane. By employing state-of-the-art techniques like FSI-FRET, we elucidated the mechanisms governing this interaction and, by western blotting, downstream signaling pathways. These insights emphasize the potential of AfHER2-lFGF2 as a promising therapeutic agent for targeting HER2, FGFRs, and HER2/FGFRs-positive cancers. This approach paves the way for targeted therapies in addressing the prevalent global health challenge of breast cancer. Citation Format: Mateusz Adam Krzyscik, Kalina Hristova. HER2-FGFR1 interaction induced by bispecific molecules: A novel strategy for treating breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1917.