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Josh Drago, MD, MS

@joshdragomd.bsky.social

260 followers 75 following 7 posts

Breast Cancer Specialist Clinical and Translational Investigator Memorial Sloan Kettering Cancer Center

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Josh Drago, MD, MS @joshdragomd.bsky.social · 1d

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

Josh Drago, MD, MS @joshdragomd.bsky.social · 1d

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 · 1d

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.

Josh Drago, MD, MS @joshdragomd.bsky.social · 1d

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

Josh Drago, MD, MS @joshdragomd.bsky.social · 1d

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.

Josh Drago, MD, MS @joshdragomd.bsky.social · 1d

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.

Josh Drago, MD, MS @joshdragomd.bsky.social · 1d

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

aacrjournals.org/cancerdiscov...

Trastuzumab Deruxtecan (T-DXd) Resistance via Loss of HER2 Expression and Binding

Abstract. T-DXd is clinically beneficial in HER2 positive and HER2 low metastatic breast cancer. However, therapeutic resistance emerges over time in most patients, with poorly defined resistance mech...

aacrjournals.org

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Reposted by Josh Drago, MD, MS

Sarat Chandarlapaty @saratchandarlapaty.bsky.social · May 16

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:/...

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...

urldefense.com

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Reposted by Josh Drago, MD, MS

Sarat Chandarlapaty @saratchandarlapaty.bsky.social · Dec 12

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

Sarah Sammons MD @drsarahsammons.bsky.social · Dec 9

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/...

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...

ascopubs.org

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Reposted by Josh Drago, MD, MS

Tatiana Prowell, MD @tmprowell.bsky.social · Nov 12

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...

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...

www.cell.com

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