SNX10 deficiency impairs sensitivity to anti-HER2 antibody–drug conjugates via altering HER2 trafficking in HER2-positive breast cancer

Antibody-drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable efficacy in breast cancer. Despite the promising efficacy of anti-HER2 ADCs, many patients are still experiencing disease progression under treatment. Here, by analyzing the transcriptome data from patient-derived organoid models, I-SPY2 trial, and resistant cell lines, we identified that SNX10 deficiency conferred anti-HER2 ADCs resistance in HER2-positive breast cancer. Low levels of SNX10 attenuated HER2 recycling and promoted HER2 trafficking into lysosomes. Furthermore, we found the underlying mechanism of SNX10 in HER2 traffic by regulating the endosomal RAB11A. We propose that SNX10 deficiency contributes to the inhibition of HER2 recycling as well as the decrease of cell-surface HER2 and causes anti-HER2 ADC resistance.