Leveraging radiation to sensitize breast cancers to T-DXd

While HER2+ breast cancers (BCs) can be therapeutically targeted via HER2-targeted agents, response depends on HER2 status; tumors with residual HER2 expression (HER2-low) do not respond. HER2-low status have been described in triple negative (TNBC) and HR+ BCs, and includes primary tumors, metastases, and circulating tumor cells (CTCs). Recently, patient benefit has expanded to HER2-low tumors with the development of HER2-targeted antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd), which suggest that the presence of a small reservoir of HER2+ cells is therapeutically actionable. This is of upmost importance, considering an estimated 50% of all diagnosed BCs are actually HER2-low. CTCs isolated and cultured from HER2-, metastatic HR+ and TNBC patients can divide to produce HER2+ cells with as few as 3 population doublings, without the acquisition of genomic alterations that activate HER2. Similar results were obtained from HER2+ CTCs, which can yield HER2- daughter cells with similar division kinetics. These results demonstrate HER2 expression is plastic and suggest that HER2- and HER2-low BCs may respond to T-DXd at least in part because of the maintenance of a heterogeneous HER2 state. Thus, designing treatment strategies to maximize therapeutic benefit to T-DXd in the HER2-/low patient population remains an unmet clinical need. We and others have found HER2 plasticity in cell culture models and CTCs derived from HER2- BC. We recently observed that ionizing radiation (IR) increases HER2 expression and HER2 heterogeneity in HER2- BC models. We also find that IR increases cell death when paired when T-DXd in models of HER2- BC. Taken together, we hypothesize that IR sensitizes models of HER2- and HER2-low BC to the HER2- targeted ADC T-DXd. To test this hypothesis, we will employ established cell culture and CTC models of heterogeneous HER2- and HER2-low BCs. We will first determine the extent to which IR sensitizes these models to T-DXd. Transcriptomics post-IR will provide insight into how IR remodels gene expression to support HER2 plasticity. Using these in vitro models, we will test whether IR sensitizes BCs to T-DXd. These studies will inform which patient populations may benefit from combined IR and T-DXd based on HER2 expression. We will then pivot and investigate whether IR sensitizes in vivo models of HER2-/low BC to T-DXd, by examining whether IR coupled with T-DXd reduces tumorigenesis and extends survival. Correlative studies will be performed to examine the duration of elevated intratumoral HER2 expression and heterogeneity to define the optimal time window for IR prior to T-DXd. We will then examine whether IR can resensitize T-DXd-resistant tumor models to T-DXd. These studies will provide insight into the timelines and context(s) that IR can be used to stimulate a therapeutic response to T-DXd, which could be leveraged for future investigator-initiated clinical trials. Project Number: 1R21CA307807-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jennifer Spangle | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $402,401 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-E (82)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11284799