Josh Drago, MD, MS

@saratchandarlapaty.bsky.social @avantikagupta.bsky.social @theaacr.bsky.social

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!

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.

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

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.

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.

In this manuscript, online today in Cancer Discovery, we investigate target-mediated resistance to ADCs, and propose ways to overcome it.

aacrjournals.org/cancerdiscov...

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...

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:/...

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

Development and Validation of the RSClinN+ Tool to Predict Prognosis and Chemotherapy Benefit for Hormone Receptor–Positive, Node-Positive Breast Cancer PURPOSEClinicopathological factors and the 21-gene Oncotype DX Breast Recurrence Score (RS) test both influence prognosis. Our goal was to develop a new tool, RSClinN+, to individualize recurrence ris...

RSclin for node positive ER+ patients is validated! I hope it’s available to use soon.

Always helpful to have tools to estimate recurrence and chemo benefit in these hard conversations with patients!

ascopubs.org/doi/10.1200/...

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...

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...