33P - Visualizing trastuzumab-deruxtecan action in HER2+ breast cancer cells at nanoscale

Background

Breast cancers that test positive for the human epidermal growth factor receptor 2 (HER2+) are known to be highly aggressive and hold poor survival rates. However, advances in therapies targeting HER2 have led to anti-HER2 antibodies like Trastuzumab and tyrosine kinase inhibitors. Trastuzumab-deruxtecan (Tz-Dxd) is an antibody-drug conjugate that has shown remarkable results in both HER2+ and HER2-low BCa. By promoting its internalization and trafficking to lysosomes through HER2 binding, Tz-Dxd has great potential to revolutionize cancer treatment.

Methods

This study aimed to investigate the effects of Tz-Dxd on HER2+ breast cancer cell lines at the nanoscale level using high-resolution light and electron microscopy techniques, biochemistry and flow cytometry analysis.

Results

We found that after 2 hours, Tz-Dxd induced ERBB2 phosphorylation and downstream signaling activation without significant internalization of the receptor. However, the receptor was internalized towards lysosomes at later stages (72 hours), but only in a limited fraction of cells. Nonetheless, Tz-Dxd induced apoptosis in more than 50% of cells after 72 hours of treatment, even in cells where ERBB2/Tz-Dxd was not internalized. This suggests that deruxtecan was efficiently released from Tz in lysosomes reaching by diffusion surrounding cells. In addition to apoptotic cells, we observed a consistent fraction of cells displaying suggestive hallmarks of senescence. In particular, we detected dramatic cell flattening, increased nuclear size, chromatin reorganization, nuclear envelope ruptures and expansion of the lysosomal compartment. Cells also displayed alterations of the mitochondrial network dynamics and induction of autophagy; indicative of an elevated energy demand to sustain autophagy and senescence.

Conclusions

These results suggest that Tz-Dxd has potent anti-tumor activity in vitro but might also induce cellular senescence, which would merit further investigation due to its uncertain role in cancer progression in the long run.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Academic group.

Funding

Has not received any funding.

Disclosure

O. Garrone: Financial Interests, Institutional, Advisory Board: Eisai, MSD, Daiichi Sankyo, Gilead; Financial Interests, Personal, Financially compensated role: Novartis, Pfizer, Lilly. All other authors have declared no conflicts of interest.