HER2 ADC resistance driven by IL-17 signaling and ROR1 upregulation: Overcoming DS-8201 resistance with BRY812 and BR111

DS-8201 (Trastuzumab Deruxtecan), a milestone antibody-drug conjugate, has demonstrated reputable efficacy in various solid tumors, particularly in patients with HER2-low and HER2-ultralow expression. However, its widespread application has been accompanied by increasingly prominent drug resistance. To investigate the resistance mechanism towards DS-8201, we successfully established DS-8201-resistant cell lines in breast cancer and in lung cancer, and performed mechanistic investigations on HER2 expression change, DS-8201 internalization efficiency, cross-resistance to DXd as well as ABC transporters expression. Results revealed that these mechanism were observed in both resistant cell lines expect for DXd-resistance, which was only found in breast cancer. Furthermore, we selected lung cancer resistant cell line to perform RNA-seq analysis and found IL-17 signaling as major contributing pathway, with CXCL1 and LCN2 being the mostly affected genes. Literature research revealed possible mechanism includes tumor microenvironment remodeling, enhanced cell survival, and immune evasion.BRY812 (an anti-LIV1 ADC conjugated to MMAE) and BR111 (an anti-ROR1 ADC conjugated to eribulin) are novel ADCs that have shown potent antitumor activity in various solid tumors. Ours studies with both resistant cell lines and corresponding CDX models demonstrated that both BRY812 and BR111 can effectively overcome DS-8201 resistance. Further investigation revealed that treatment with HER2-targeting ADCs (DS-8201 and T-DM1) dose-dependently upregulated ROR1 expression, providing a potential mechanism for BR111's efficacy in this resistant setting. In conclusion, our research findings collectively revealed DS-8201 resistance mechanism and provided evidence that BRY812 and BR111 can overcome DS-8201 resistance.