Dataset Information

HER2-positive breast cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300628 | GEO | 2026/03/20

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

HER2-positive breast cancer

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets