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CB2R downregulation drives trastuzumab resistance by reorganizing HER2 dimers to evade IFN-γ and enhance EGFR signaling

ABSTRACT: Despite the remarkable advances that have been implemented in HER2+ breast cancer treatment, especially upon the development of monoclonal antibodies like trastuzumab, resistance to HER2-targeted therapies remains a significant clinical challenge. Here, we investigated the role of the endocannabinoid system, specifically the cannabinoid CB2 receptor (CB2R), in trastuzumab resistance mechanisms. Analysis of human breast cancer samples revealed that a decreased expression of HER2-CB2R heterodimers following neoadjuvant treatment, primarily due to CB2R downregulation, is linked to poor long-term patient outcomes. Using various cellular and animal models, we demonstrate that trastuzumab resistance is dependent on CB2R expression, as it occurs upon CB2R downregulation and is rescued by CB2R re-expression. Mechanistically, CB2R loss enables cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB2R to HER2-EGFR heterodimers, thus reducing dependence on HER2 signaling and increasing reliance on EGFR-mediated pathways. Moreover, EGFR inhibition resensitized resistant cells to trastuzumab. In sum, our findings (a) identify a novel mechanism of trastuzumab resistance involving CB2R-mediated receptor heterodimerization and IFN-γ signaling modulation, (b) establish HER2-CB2R/EGFR heterodimer status and CB2R/EGFR expression as potential predictive biomarkers, and (c) support dual HER2/EGFR targeting as a promising strategy to overcome trastuzumab resistance in patients with HER2+ breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300749 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Faratian2009 - Role of PTEN in Trastuzumab resistance This model is described in the article: Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Faratian D, Goltsov A, Lebedeva G, Sorokin A, Moodie S, Mullen P, Kay C, Um IH, Langdon S, Goryanin I, Harrison DJ. Cancer Res. 2009 Aug; 69(16): 6713-6720 Abstract: Resistance to targeted cancer therapies such as trastuzumab is a frequent clinical problem not solely because of insufficient expression of HER2 receptor but also because of the overriding activation states of cell signaling pathways. Systems biology approaches lend themselves to rapid in silico testing of factors, which may confer resistance to targeted therapies. Inthis study, we aimed to develop a new kinetic model that could be interrogated to predict resistance to receptor tyrosine kinase (RTK) inhibitor therapies and directly test predictions in vitro and in clinical samples. The new mathematical model included RTK inhibitor antibody binding, HER2/HER3 dimerization and inhibition, AKT/mitogen-activated protein kinase cross-talk, and the regulatory properties of PTEN. The model was parameterized using quantitative phosphoprotein expression data from cancer cell lines using reverse-phase protein microarrays. Quantitative PTEN protein expression was found to be the key determinant of resistance to anti-HER2 therapy in silico, which was predictive of unseen experiments in vitro using the PTEN inhibitor bp(V). When measured in cancer cell lines, PTEN expression predicts sensitivity to anti-HER2 therapy; furthermore, this quantitative measurement is more predictive of response (relative risk, 3.0; 95% confidence interval, 1.6-5.5; P < 0.0001) than other pathway components taken in isolation and when tested by multivariate analysis in a cohort of 122 breast cancers treated with trastuzumab. For the first time, a systems biology approach has successfully been used to stratify patients for personalized therapy in cancer and is further compelling evidence that PTEN, appropriately measured in the clinical setting, refines clinical decision making in patients treated with anti-HER2 therapies. This model is hosted on BioModels Database and identified by: BIOMD0000000424. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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CB2R downregulation drives trastuzumab resistance by reorganizing HER2 dimers to evade IFN-γ and enhance EGFR signaling

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