Role of SNX10 in Modulating HER2 Sensitivity

Recent studies have highlighted SNX10 as a pivotal player in the resistance mechanism against ADCs targeting HER2. RNA sequencing data from various HER2-positive breast cancer models have revealed a correlation between low SNX10 expression and reduced sensitivity to ADCs such as T-DM1 and T-DXd (Dillard et al., 2025). SNX10 is known for its involvement in vesicle transport and endosomal trafficking, essential processes for maintaining appropriate HER2 levels on the cell surface.

The downregulation of SNX10 enhances lysosomal degradation of HER2, leading to diminished cell-surface HER2 levels, which is critical for ADC efficacy. Experiments conducted on patient-derived organoids (PDOs) and SKBR3-TR cells confirmed that SNX10 deficiency promotes HER2 internalization and lysosomal degradation, thereby conferring resistance to anti-HER2 therapies (Dillard et al., 2025).

Mechanisms of HER2 Degradation in Breast Cancer

Understanding HER2 degradation mechanisms is essential to address ADC resistance. HER2 undergoes degradation via two primary pathways: the ubiquitin-proteasome system and lysosomal degradation. In the context of SNX10 deficiency, the lysosomal pathway becomes predominant, leading to accelerated HER2 degradation (Dillard et al., 2025). This phenomenon is particularly pronounced in resistant PDOs where the expression of vesicle trafficking-related genes is altered.

Gene Set Variation Analysis (GSVA) has revealed that both resistant PDOs and non-pathological complete response (non-pCR) patients from the I-SPY2 trial exhibit abnormal levels of HER2 signaling pathways and disrupted intracellular trafficking pathways. These findings suggest that targeting these aberrant pathways could restore sensitivity to anti-HER2 ADCs (Dillard et al., 2025).

Insights from RNA Sequencing on HER2-Positive Tumors

RNA-sequencing studies have provided significant insights into the transcriptomic landscape of HER2-positive tumors. Analysis of tumor samples from the I-SPY2 trial identified 283 differentially expressed genes (DEGs) associated with resistance to T-DM1 (Dillard et al., 2025). This dataset revealed a strong enrichment for pathways related to vesicle transport, highlighting the importance of intracellular trafficking in modulating HER2 levels.

Differential expression of SNX10 and RAB11A, a key regulator of receptor recycling, was identified as a potential mechanism underlying ADC resistance. In the presence of low SNX10 levels, RAB11A expression decreases, leading to impaired HER2 recycling and increased HER2 lysosomal degradation (Dillard et al., 2025).

Therapeutic Potential of Nonhallucinogenic Psychoplastogens

Emerging research into psychoplastogens offers promising avenues for enhancing treatment outcomes in breast cancer. Compounds such as JRT, a nonhallucinogenic analogue of LSD, have been shown to promote neuroplasticity without the associated hallucinogenic effects (Tuck et al., 2025). The potential application of these compounds in cancer therapy is under investigation, as they may enhance the efficacy of existing treatments through mechanisms involving synaptic plasticity and cellular resilience.

The integration of psychoplastogens into cancer treatment regimens could provide a novel approach to overcoming resistance mechanisms by potentially improving the responsiveness of cancer cells to targeted therapies.

Conclusion

The multifaceted mechanisms underlying resistance to anti-HER2 ADCs highlight the need for innovative therapeutic strategies. Targeting SNX10 and elucidating its role in HER2 trafficking and degradation could pave the way for enhancing the efficacy of ADCs in HER2-positive breast cancer. Furthermore, the exploration of nonhallucinogenic psychoplastogens may provide additional tools to combat treatment resistance and improve patient outcomes.

References

1. Dillard, C., Teles-Reis, J., Jain, A., Khezri, R., Micheli, S., & Rusten, T. E. (2025). SNX10 deficiency impairs sensitivity to anti-HER2 antibody–drug conjugates via altering HER2 trafficking in HER2-positive breast cancer. Proceedings of the National Academy of Sciences of the United States of America

2. Tuck, J. R., Dunlap, L. E., Khatib, Y. A., Hatzipantelis, C. J., Weiser Novak, S., & Olson, D. E. (2025). Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential. Proceedings of the National Academy of Sciences of the United States of America

FAQ

What is SNX10, and why is it important in breast cancer treatment?

SNX10 is a protein involved in vesicle transport and endosomal trafficking. Its expression levels have been linked to the sensitivity of HER2-positive breast cancer cells to antibody-drug conjugates (ADCs). Low levels of SNX10 are associated with increased HER2 degradation and resistance to ADCs.

How do HER2-targeting ADCs work?

HER2-targeting ADCs work by delivering cytotoxic drugs directly to HER2-expressing cancer cells. The ADC binds to HER2 on the cell surface, is internalized, and releases the cytotoxic agent within the cell, leading to cell death.

What are psychoplastogens, and how might they be used in cancer therapy?

Psychoplastogens are compounds that promote neuroplasticity and may enhance the responsiveness of cells to treatment. Nonhallucinogenic analogues, like JRT, could potentially improve cancer treatment outcomes by supporting cellular resilience and enhancing therapeutic efficacy.

What are the potential next steps in research regarding ADC resistance?

Future research could focus on further elucidating the molecular mechanisms of SNX10 and other related proteins in HER2 trafficking and degradation. Additionally, exploring the integration of psychoplastogens into treatment regimens for breast cancer could yield promising results.