Paolo Tarantino, Clinical Research Fellow at Dana-Farber Cancer Institute, shared on LinkedIn:
“Proud to have presented the CHARISMA study as a Rapid Oral at ESMO26 in Madrid!
Why do TOPO1 ADCs stop working? And how can we overcome resistance?
We performed multiomic profiling of 26 paired biopsies collected before and after progression on T-DXd and/or SG.
Three key findings:
- Target loss is not the whole story. HER2 expression frequently decreased after T-DXd, but remained detectable in all evaluable tumors, and no consistent Trop2 decrease was seen after SG.
- Drug efflux matters. Acquired ABCB1/ABCC1 amplifications emerged at progression, with functional studies confirming their role in T-DXd resistance.
- Internalization matters too. MAN2A2 downregulation impaired T-DXd internalization and reduced sensitivity in preclinical models.
The takeaway: ADC resistance is multifactorial. Payload-related resistance is key, with important implications for how we develop and sequence ADCs.
Grateful to my incredible collaborators at DFCI and AstraZeneca Translational Medicine, especially Maurizio S., whose support was instrumental in making this study possible.
Special thanks also to Pedram Razavi from MSK for his insightful discussion and perspectives on our findings!
And above all, grateful to the patients who entrust us with their data and samples to help advance cancer research.”
You can also read: 25 Posts Not to Miss from ESMO Congress 2026: Day 4
