Hormone receptor-positive breast cancer often responds to endocrine therapy at first, which is lovely in the way umbrellas are lovely until the hurricane arrives. Over time, many tumors learn new tricks and stop listening. One accomplice is HER3, a cell-surface receptor that shows up in a lot of breast cancers and has a reputation for helping tumors stay alive, dodge treatment, and generally behave like the coworker who never does the project but still takes credit.

The new paper by Xie and colleagues, published April 15, 2026, asks a sharp pharmacology question: what if you hit HER3-positive, hormone receptor-positive breast cancer with patritumab deruxtecan, also called HER3-DXd, and at the same time block ATR, one of the cell’s main DNA damage emergency managers? [1]

That pairing makes molecular sense. HER3-DXd is an antibody-drug conjugate, which is science’s way of saying “guided missile with paperwork.” The antibody homes in on HER3, gets swallowed by the cancer cell, and then releases a deruxtecan payload derived from a topoisomerase I inhibitor. Topoisomerase I normally helps DNA unwind without snapping itself into chaos. Inhibiting it creates DNA stress. Lots of it. ATR, meanwhile, is one of the kinases that rushes in when replication forks wobble and DNA starts behaving like a Jenga tower in a moving car. Block ATR, and the cell gets much worse at surviving that stress.

So yes, this paper is basically about handing the tumor a lit fuse and then confiscating the fire extinguisher.

HER3-DXd: targeted delivery with a mean streak

HER3 is a bit of an odd duck. Unlike some of its flashier receptor relatives, its own kinase activity is weak, but it is still excellent at partnering up and pushing downstream survival signaling, especially through the PI3K-AKT pathway. In breast cancer, that makes it a frequent side character in resistance stories, which is annoying because side characters are never supposed to run the whole plot.

HER3-DXd has already shown activity in breast cancer. In a prior phase I/II trial, it produced responses across breast cancer subtypes, including hormone receptor-positive, HER2-negative disease [2]. In the more recent ICARUS-BREAST01 phase II study, published in Nature Medicine in 2025, HER3-DXd showed considerable activity in patients with HR+/HER2-negative metastatic disease after CDK4/6 inhibitors and chemotherapy, with a manageable safety profile [3]. Earlier “window” studies in early HR+/HER2-negative disease also suggested the drug can suppress proliferation and stir biologic changes after even a short exposure [4,5].

So the drug already had credentials. This new paper asks how to make it nastier to the tumor.

ATR: the panic button you do not want the tumor pressing

ATR is one of the major guardians of replication stress. When cells copy DNA and things go sideways, ATR slows the cell cycle, coordinates repair, and tries to stop catastrophe. In normal biology, that is responsible adult behavior. In cancer biology, it can become extremely inconvenient, because tumor cells often live on the edge of replication disaster already and use ATR as a full-time crisis manager.

Xie and colleagues found that combining HER3-DXd with the ATR inhibitor BAY 1895344 boosted DNA damage, increased sub-G1 arrest, pushed cells toward apoptosis, and suppressed tumor growth in mouse xenograft models more than either treatment alone [1]. They saw this in both standard breast cancer cell lines and tamoxifen-resistant versions, which is the part likely to make oncologists lean a little closer to the screen.

In plain English: HER3-DXd roughs up the cancer cell’s DNA. ATR inhibition then removes one of the cell’s best survival routines. The result is less “minor inconvenience” and more “computer blue screen at the molecular level.”

Why this matters outside the lab coat

The big attraction here is not just more killing. It is selective more killing. If HER3 helps direct the payload into the tumor, and ATR inhibition exploits the tumor’s heavy reliance on damage control, the combination could hit a population that has already become stubborn after endocrine therapy. That is a real clinical problem, not a theoretical one.

There is a catch, because of course there is. This study is preclinical. Cells in dishes are useful, but they do not have jobs, families, or livers. Mice are useful too, but they are also not people. We do not yet know whether this exact combo will deliver enough benefit in patients to justify the added toxicity that DNA-damage-targeting strategies can bring. That is the eternal pharmacology party trick: every molecule looks charming until the safety data arrive.

Still, the direction is compelling. As of August 27, 2025, a phase III trial called HERTHENA-Breast04 had begun enrolling patients with HR-positive, HER2-negative metastatic breast cancer for patritumab deruxtecan in a later-line setting [6]. This new paper adds a mechanistic argument for rational combinations, especially in endocrine-resistant disease where the tumor has already shown it enjoys improvising.

Cancer cells love contingency plans. This study tries to cancel the reservation.

References

1. Xie X, Lee J, Gi YJ, et al. ATR inhibition potentiates the antitumor efficacy of HER3-DXd in HER3-positive/HR-positive breast cancer by increasing DNA damage. Br J Cancer. 2026. DOI: https://doi.org/10.1038/s41416-026-03413-1

2. Krop IE, Hamilton EP, Takahashi S, et al. Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3-Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3-Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial. J Clin Oncol. 2024;42. PMCID: https://pmc.ncbi.nlm.nih.gov/articles/PMC10730028/

3. Jerusalem G, Miglietta F, Bardia A, et al. Patritumab deruxtecan in HR+HER2-negative advanced breast cancer: a phase 2 trial. Nat Med. 2025. DOI: https://doi.org/10.1038/s41591-025-03885-3

4. Oliveira M, Falato C, Cejalvo JM, et al. Patritumab deruxtecan in untreated hormone receptor-positive/HER2-negative early breast cancer: final results from part A of the window-of-opportunity SOLTI TOT-HER3 pre-operative study. Ann Oncol. 2023;34(8):670-680. DOI: https://doi.org/10.1016/j.annonc.2023.05.004

5. Brasó-Maristany F, Ferrero-Cafiero JM, Falato C, et al. Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response. Nat Commun. 2024;15:5826. DOI: https://doi.org/10.1038/s41467-024-50056-y

6. Fusco N, Criscitiello C, Curigliano G. Patritumab deruxtecan in breast cancer treatment: a drug evaluation. Expert Opin Biol Ther. 2025. PMCID: https://pmc.ncbi.nlm.nih.gov/articles/PMC12758208/

Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.