HER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-based PET Imaging

Purpose: Recent studies have highlighted a role of human epidermal growth factor receptor 3 (HER3) in HER2-driven cancers (e.g. breast cancer) implicating the up-regulation of the receptor in resistance to HER-targeted therapies and Hsp90 inhibitors (e.g. AUY922). Therefore, we have developed an affibody-based PET radioconjugate that quantitatively assesses HER3 changes induced by Hsp90 inhibition in vivo. Experimental Design: Z_HER3:8698 affibody molecules were conjugated via the C-terminus cysteine to DFO-maleimide for ⁸⁹Zr radiolabeling. The probe was characterized in vitro and in vivo in a panel of human breast cell lines and xenograft models with varying HER3 receptor levels. Additionally, the radioconjugate was investigated as a tool to monitor the outcome of AUY922, an Hsp90 inhibitor in MCF-7 xenograft model. Results: We demonstrated that ⁸⁹Zr-DFO-Z_HER3:8698 can track changes in receptor expression in HER3-positive xenograft models and monitor the outcome of AUY922 treatment. Our in vitro findings showed that MCF-7 cells, which are phenotypically different from BT474, develop resistance to AUY922 through HER3/IGF-1Rb-mediated signaling. Of note, the lack of response in vitro due to HER3 recovery was confirmed in vivo using ⁸⁹Zr-DFO-Z_HER3:8698-based imaging. Upon AUY922 treatment, higher radioconjugate uptake was detected in treated MCF-7 xenografts, correlating with an AUY922-induced HER3 up-regulation concomitant with an increase in IGF-1Rb expression. Conclusion: These data underline the potential of HER3-basedPET imaging to noninvasively provide information about HER3 expression and to identify patients not-responding to targeted therapies due to HER3 recovery.

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