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Josh Drago, MD, MS @joshdragomd.bsky.social · 10/11/2025

ADC resistance is likely heterogeneous, and the phenomena above may explain only a portion of cases. But these early clues can inform prospective trail efforts, as well as ADC sequencing strategies. There is much more to come!

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Josh Drago, MD, MS @joshdragomd.bsky.social · 10/11/2025

To overcome this, we investigated giving low-dose multi-target ADC combinations, which ‘hedges’ against target-mediated resistance and allows for more consistent payload delivery.

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Josh Drago, MD, MS @joshdragomd.bsky.social · 10/11/2025

We modeled HER2 loss in isogenic laboratory models, which clearly compromised T-DXd internalization and cytotoxicity, leading to drug resistance.

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Josh Drago, MD, MS @joshdragomd.bsky.social · 10/11/2025

More broadly, distinct HER2 downregulation was observed in a significant subset of patients with breast cancer treated with T-DXd, and seems more prevalent/pronounced in patients with HER2-low disease. This trend was not observed with Sacituzumab Govitecan in our cohort.

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Josh Drago, MD, MS @joshdragomd.bsky.social · 10/11/2025

We report three cases of resistance to T-DXd underpinned by mutations in the trastuzumab binding domain. These cases are rare, but illustrative of the evolutionary pressure generated by a highly effective HER2-targeted therapy.

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Reposted by Josh Drago, MD, MS

Sarat Chandarlapaty @saratchandarlapaty.bsky.social · 16/05/2025

Published online today - work from our team led by Avantika Gupta, revealing how APOBEC3 mutagenesis promotes resistance to several targeted therapies in breast cancer. Check it out! urldefense.com/v3/__https:/...

urldefense.com

APOBEC3 mutagenesis drives therapy resistance in breast cancer

Nature Genetics - Analysis of a large cohort of metastatic breast cancer samples shows that APOBEC mutational signatures are enriched in post-treatment samples. APOBEC activity was also associated...

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Reposted by Josh Drago, MD, MS

Sarat Chandarlapaty @saratchandarlapaty.bsky.social · 12/12/2024

Fantastic presentation #SABCS by @avantikagupta.bsky.social on apobec3 in breast cancer. Demonstrating the role of this process in promoting therapy resistance.

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Reposted by Josh Drago, MD, MS

Tatiana Prowell, MD @tmprowell.bsky.social · 12/11/2024

NEW #Oncology: EGFR expression mediates resistance to T-DXd (EGFR overexpression ⬇️ HER2 homodimerization & HER2/ADC internalization) Combining with EGFR mAbs restored HER2/ADC trafficking & ⬆️ activity in nonclinical models #DrugDevelopment #OncoSky www.cell.com/cell-reports...

cell.com

EGFR-directed antibodies promote HER2 ADC internalization and efficacy

Gupta et al. demonstrate that high EGFR expression mediates resistance to HER2 antibody drug conjugates (ADCs) including trastuzumab deruxtecan (T-DXd) by limiting HER2/ADC internalization. The additi...

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