SNX10 deficiency impairs sensitivity to anti-HER2 antibody–drug conjugates via altering HER2 trafficking in HER2-positive breast cancer
Menée à l'aide de lignées cellulaires et d'organoïdes dérivés de tumeurs de patientes atteintes d'un cancer du sein HER2+, cette étude met en évidence un mécanisme par lequel un faible niveau d'expression de la protéine SNX10 réduit la sensibilité des cellules cancéreuses aux conjugués anticorps-médicaments anti-HER2 en altérant le recyclage du récepteur HER2 et le transport de ce dernier dans les lysosomes
In this study, by analyzing the transcriptome data from patient-derived organoid models, I-SPY2 trial, and resistant cell lines, we identified that SNX10 deficiency impairs sensitivity to anti-HER2 antibody–drug conjugates (ADCs) in HER2-positive breast cancer. Low levels of SNX10 attenuated HER2 recycling and promoted HER2 trafficking into lysosomes and being degraded. In general, the lack of SNX10 inhibited HER2 recycling by downregulating RAB11A, decreased cell-surface HER2, and caused cross-resistance to anti-HER2 drugs. Our study revealed an underlying mechanism of anti-HER2 ADCs and identified SNX10 as a potential biomarker for anti-HER2 ADC resistance 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.
Proceedings of the National Academy of Sciences , article en libre accès 2025