Spatial proteogenomics reveals S100-RAGE axis as a druggable mediator of trastuzumab deruxtecan resistance in metastatic breast cancer.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE327983 | GEO | 2026/06/01
REPOSITORIES: GEO
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Project description:Trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody-drug conjugate with a topoisomerase I inhibitor connected by a cleavable linker, has been approved for patients with HER2-positive gastric or gastroesophageal junction tumors. This biomarker study assessed HER2 expression and immune cell infiltration in relation to the therapeutic response to T-DXd. This retrospective analysis included samples from patients treated with T-DXd in three clinical trials. We performed RNA sequencing and multiplex immunohistochemistry on archival tumor samples obtained at baseline, during treatment, and after treatment. Flow cytometry was performed on tumor infiltrating immune cells freshly isolated from tumor tissues. Samples from 28 patients were included in this study. ERBB2 mRNA levels and CD20+ cell infiltration in tumors were significantly higher at baseline in responders than in nonresponders. Patients were classified into three biological groups based on their baseline tumor/stroma-infiltrating immune cell densities. Two groups reported similar response rates, but a trend was observed toward a shorter progression-free-survival in the group with more immunosuppressive regulatory T cells and programmed death-ligand 1 (PD-L1) expression at baseline. T-DXd treatment tended to increase the levels of tumor-infiltrating CD8+ T cells and PD1+CD8+ T cells, particularly in responders. Gene expression signatures of CTL and helper T cells increased during treatment, whereas signatures related to hypoxia, MYC targets, collagen formation, and interleukin-10 were downregulated. Our data suggest that HER2 expression levels and baseline tumor microenvironment (TME) characteristics correlate with T-DXd efficacy. Furthermore, this treatment may modulate TME immune profiles. Further validation using a larger sample size is warranted.
2024-12-16 | GSE262648 | GEO
Project description:Spatial proteogenomics reveals S100-RAGE axis as a druggable mediator of trastuzumab deruxtecan resistance in metastatic breast cancer.
| PRJNA1453451 | ENA
Project description:This study will evaluate the efficacy, safety, and pharmacokinetics of Trastuzumab deruxtecan (T-DXd) in participants with human epidermal growth factor 2 (HER2)-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC).
| 2366623 | ecrin-mdr-crc
Project description:HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. While HER2-directed therapies like fam-trastuzumab deruxtecan (T-DXd) are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer (PC) and urothelial carcinoma (UC) remains inadequately characterized.This study demonstrates that HER2 is rarely overexpressed in metastatic prostate cancer but is more common and consistent in urothelial carcinoma. These findings highlight the need for HER2 testing in urothelial cancer.
2025-07-28 | GSE300195 | GEO
Project description:Despite the clinical success of trastuzumab deruxtecan (T-DXd) in treating HER2-positive gastric cancers (GCs), its precise immunomodulatory mechanisms remain elusive. This study investigates T-DXd's immune-related actions in GC cells through RNA sequencing.
2024-10-20 | GSE245851 | GEO
Project description:Purpose: Novel antibody-drug conjugates (ADCs) have shown potent antitumor activity across multiple cancer types. Here, we aimed to identify potential determinants of response to patritumab deruxtecan (HER3-DXd), a HER3-directed ADC linked to a potent topoisomerase I inhibitor (TOP1i) payload, in breast cancer (BC) patient-derived xenograft (PDX) models. Experimental Design: The antitumor activity of HER3-DXd was assessed in 31 BC PDXs and classified according to tumor growth inhibition and duration of response. We analyzed the sensitivity to HER3-DXd according to the molecular characteristics of the PDX models, the sensitivity to the TOP1i irinotecan, and prior patient treatments. The biological effects following treatment with HER3- DXd were assessed and associated to treatment response. Results: Fourteen out of 31 (45%) PDXs exhibited a profound and sustained response to HER3-DXd. Basal-like PAM50 intrinsic subtype was associated with long-term response, across HER3/ERBB3 expression levels. We also observed a positive association between HER3-DXd and irinotecan sensitivity in the PDXs, as well as short-lasting antitumor response in models derived from patients with prior repeated exposure to chemotherapy. HER3-DXd showed sustained activity in BRCA1/BRCA2-mutated PARPi-resistant PDX models. Long-term responders exhibited persistent DNA damage and lacked early transcriptional activation of the G2/M cell cycle checkpoint to allow for DNA repair and R-loop resolution, in parallel resulting in immune pathways activation. Conclusions: HER3-DXd exhibited potent antitumor activity in breast cancer PDX models, including those with BRCA1/BRCA2 alterations and PARPi resistance. Notably, characteristics linked to long-term response were primarily associated with the TOP1i payload activity.
2025-11-28 | GSE307574 | GEO
Project description:Trastuzumab deruxtecan (T-DXd) is an anti-HER2 (human epidermal growth factor receptor 2) antibody-drug conjugate which has previously shown efficacy in patients with HER2-overexpressing and HER2-low metastatic breast cancer (mBC). However, the mechanisms of action and resistance of this drug remain partially unclear. DAISY (NCT04132960) is a phase II, open-label study that included patients with mBC whose disease progressed after at least one line of chemotherapy in the metastatic setting. Patients were enrolled in three cohorts according to HER2 expression determined by immunohistochemistry (IHC); cohort 1: HER2-overexpressing (HER2 IHC 3+ or HER2 IHC 2+/ISH+, n=72), cohort 2: HER2-low (HER2 IHC2+/ISH- or HER2 IHC 1+, n=74), and cohort 3: HER2 IHC 0 mBC (n=40). Patients were treated with T-DXd 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. In the full analysis set population (n=177), the confirmed objective response rate (ORR) was of 70.6% (95% CI: 58.3-81) in cohort 1, 37.5% (95% CI: 26.4-49.7) in cohort 2, and 29.7% (95% CI: 15.9-47) in cohort 3 (p <0.0001). The median progression-free survival (PFS) was 11.1 months (95% CI: 8.5-14.4) in cohort 1, 6.7 months (95% CI: 4.4-8.3) in cohort 2, and 4.2 months (95% CI: 2-5.7); in cohort 3. Cohort 1 was significantly associated with longer PFS (adjusted HR: 0.53, 95% IC: 0.34-0.84, p=0.007), and cohort 3 with shorter PFS (adjusted HR: 1.96, 95% IC: 1.21-3.15, p=0.006) as compared to cohort 2. Exploratory analyses showed that HER2 spatial distribution predicted T-DXd response in patients with HER2-overexpressing mBC and that the transcriptomic response to T-DXd was different according to HER2 expression. No quantitative modulation of tumor microenvironment was observed after 6 to 8 weeks of treatment. Finally, recurrent mutations of the DNA repair gene SLX4 were identified in 20% of samples at resistance (4/20) as compared to 2% in baseline samples (2/88), suggesting that SLX4 mutations could mediate secondary resistance to T-DXd. These data suggest that HER2 is a key determinant of T-DXd efficacy. However, an antitumor activity is also observed in a subgroup of patients without detectable HER2 expression and resistance could be partially mediated by payload sensitivity.
| EGAS00001006905 | EGA
Project description:Purpose: Novel antibody-drug conjugates (ADCs) have shown potent antitumor activity across multiple cancer types. Here, we aimed to identify potential determinants of response to patritumab deruxtecan (HER3-DXd), a HER3-directed ADC linked to a potent topoisomerase I inhibitor (TOP1i) payload, in breast cancer (BC) patient-derived xenograft (PDX) models. Experimental Design: The antitumor activity of HER3-DXd was assessed in 31 BC PDXs and classified according to tumor growth inhibition and duration of response. We analyzed the sensitivity to HER3-DXd according to the molecular characteristics of the PDX models, the sensitivity to the TOP1i irinotecan, and prior patient treatments. The biological effects following treatment with HER3-DXd were assessed and associated to treatment response. Results: Fourteen out of 31 (45%) PDXs exhibited a profound and sustained response to HER3-DXd. Basal-like PAM50 intrinsic subtype was associated with long-term response, across HER3/ERBB3 expression levels. We also observed a positive association between HER3-DXd and irinotecan sensitivity in the PDXs, as well as short-lasting antitumor response in models derived from patients with prior repeated exposure to chemotherapy. HER3-DXd showed sustained activity in BRCA1/BRCA2-mutated PARPi-resistant PDX models. Long-term responders exhibited persistent DNA damage and lacked early transcriptional activation of the G2/M cell cycle checkpoint to allow for DNA repair and R-loop resolution, in parallel resulting in immune pathways activation. Conclusions: HER3-DXd exhibited potent antitumor activity in breast cancer PDX models, including those with BRCA1/BRCA2 alterations and PARPi resistance. Notably, characteristics linked to long-term response were primarily associated with the TOP1i payload activity.
2025-11-28 | GSE310422 | GEO
Project description:Intratumor heterogeneity for HER2 expression and amplification, observed in up to 40% of HER2-positive breast cancer is a driver of resistance to HER2-targeted therapies. The advancement of treatment for HER2 heterogeneous tumors has been hindered by the lack of preclinical models that accurately replicate the human disease. Here we describe human HER2 heterogeneous breast cancer cell models composed of ERBB2 amplified (HER2hi) and non-amplified (HER2lo) cell populations derived from the same tumor. Utilizing these models and cellular barcoding technology, we provide evidence for subclonal cooperation between HER2hi and HER2lo subpopulations and that HER2lo cells drive resistance to HER2-targeting antibody-drug conjugates (ADC) such as T-DXd but are sensitive to HER2 kinase inhibitors. CRISPR screens in heterogeneous co-cultures identified sensitizers of HER2lo cells to T-DXd including the USP9X deubiquitinating enzyme. USP9X inhibition enhances the lysosomal targeting of HER2 to potentiate ADC payload release, diminishing tumor recurrence after T-DXd treatment. Our results elucidate the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors.
2026-03-20 | GSE300628 | GEO
Project description:Determinants of long-term response to patritumab deruxtecan (HER3-DXd) in breast cancer patient-derived xenografts.
| PRJNA1365916 | ENA