RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

Engebraaten, Olav; Yau, Christina; Berg, Kristian; Borgen, Elin; Garred, Øystein; Berstad, Maria Eb; Fremstedal, Ane Sofie Viset; DeMichele, Angela; Veer, Laura van ‘t; Esserman, Laura J.; Weyergang, Anette

doi:10.1038/s41467-021-26018-z

Cited by 11 publications

(4 citation statements)

References 36 publications

(41 reference statements)

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“…RAB5A has been recognized as a potential predictive biomarker of response to T-DM1 therapy, and proteins involved in endoplasmic reticulum transport have also been identified as promising predictive biomarkers for ADC treatment strategies, according to scholar Olav Engebraaten, who tested whether clinical response to T-DM1, measured as the pCR, correlates with RAB5A RNA expression, as measured by the I-SPY2 clinical trial (NCT01042379), as a validation experiment. Whether clinical response to T-DM1, as measured by pCR, correlates with RAB5A RNA expression, the study clearly showed a significant correlation between RAB5A expression and breast cancer patients treated with T-DM1 ( p = 0.01, LR test), which was additionally corroborated by the results of the KAMILLA clinical trial (NCT01702571) ( Engebraaten et al, 2021 ; Wolf et al, 2022 ).…”

Section: Discussion and Outlooksupporting

confidence: 58%

Advances in the study of marketed antibody-drug Conjugates (ADCs) for the treatment of breast cancer

Liang,

Zhang,

et al. 2024

Front. Pharmacol.

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Breast cancer continues to have a high incidence rate among female malignancies. Despite significant advancements in treatment modalities, the heterogeneous nature of breast cancer and its resistance to various therapeutic approaches pose considerable challenges. Antibody-drug conjugates (ADCs) effectively merge the specificity of antibodies with the cytotoxicity of chemotherapeutic agents, offering a novel strategy for precision treatment of breast cancer. Notably, trastuzumab emtansine (T-DM1) has provided a new therapeutic option for HER2-positive breast cancer patients globally, especially those resistant to conventional treatments. The development of trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) has further broadened the applicability of ADCs in breast cancer therapy, presenting new hopes for patients with low HER2 expression and triple-negative breast cancer. However, the application of ADCs presents certain challenges. For instance, their treatment may lead to adverse reactions such as interstitial lung disease, thrombocytopenia, and diarrhea. Moreover, prolonged treatment could result in ADCs resistance, complicating the therapeutic process. Economically, the high costs of ADCs might hinder their accessibility in low-income regions. This article reviews the structure, mechanism of action, and clinical trials of commercially available ADCs for breast cancer treatment, with a focus on the clinical trials of the three drugs, aiming to provide insights for clinical applications and future research.

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Section: Discussion and Outlooksupporting

confidence: 58%

Advances in the study of marketed antibody-drug Conjugates (ADCs) for the treatment of breast cancer

Liang,

Zhang,

et al. 2024

Front. Pharmacol.

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“…We demonstrate that αVβ6 integrin co-ordinates HER2 endocytosis, bioavailability and signalling: αVβ6 engagement modulates HER2 phosphorylation and signalling, RAB5 activity and triggers endocytosis of HER2, which then colocalises with RAB5-and RAB7A-positive endosomes. Moreover, this mechanism is perturbed by GDI2 inhibition, which induces constitutive HER2 endocytosis, consistent with a key role for GDI2 in co-ordinating and restricting αVβ6and RAB5-dependent HER2 trafficking (88).…”

Section: Discussionsupporting

confidence: 58%

A trafficking regulatory subnetwork governs αVβ6 Integrin-HER2 crosstalk to control breast cancer invasion and drug resistance

Morgan,

Maldonado,

Dreger

et al. 2023

Preprint

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HER2 and αVβ6 integrin are independent predictors of breast cancer survival and metastasis. We investigated αVβ6 signalling and identified an αVβ6/HER2 crosstalk mechanism, which drives invasion and is dysregulated in drug resistant HER2+ breast cancer cells. Proteomic approaches revealed ligand-bound αVβ6 recruits HER2 and a trafficking regulatory subnetwork comprising the small GTPases RAB5 and RAB7A, and the Rab regulator GDI2. We show that the RAB5/RAB7A/GDI2 functional module mediates direct crosstalk between αVβ6 and HER2, impacting receptor trafficking and signalling. Acute exposure to trastuzumab increases recruitment of the RAB5/RAB7A/GDI2 subnetwork to αVβ6, but trastuzumab resistance decouples GDI2 recruitment from this trafficking module. Consequently, GDI2, RAB5 and RAB7A cooperate to regulate migration and TGFβ activation to promote tumour cell invasion and dissemination. However, these mechanisms are dysregulated following acquired trastuzumab resistance. In patients, RAB5, RAB7A & GDI2 expression correlates with patient survival and αVβ6 expression predicts therapeutic response following breast cancer relapse. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates αVβ6-HER2 crosstalk to drive breast cancer invasion, but is subverted in trastuzumab resistant cells to drive αVβ6- and HER2-independent tumour progression.

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“…There exists controversy that in patients previously exposed to pertuzumab, the efficacy of T-DM1 could be reduced potentially. Furthermore, the team confirmed that RAB5A protein might be a promising biomarker to predict the sensitivity of T-DM1, which was verified it in selected patients in the KAMILLA study [39].…”

Section: Antibody-drug Conjugatesmentioning

confidence: 67%

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer

Liu

et al. 2023

Cancers

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The amplification of epidermal growth factor receptor 2 (HER2) is associated with a poor prognosis and HER2 gene is overexpressed in approximately 15–30% of breast cancers. In HER2-positive breast cancer patients, HER2-targeted therapies improved clinical outcomes and survival rates. However, drug resistance to anti-HER2 drugs is almost unavoidable, leaving some patients with an unmet need for better prognoses. Therefore, exploring strategies to delay or revert drug resistance is urgent. In recent years, new targets and regimens have emerged continuously. This review discusses the fundamental mechanisms of drug resistance in the targeted therapies of HER2-positive breast cancer and summarizes recent research progress in this field, including preclinical and basic research studies.

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RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

Cited by 11 publications

References 36 publications

Advances in the study of marketed antibody-drug Conjugates (ADCs) for the treatment of breast cancer

Advances in the study of marketed antibody-drug Conjugates (ADCs) for the treatment of breast cancer

A trafficking regulatory subnetwork governs αVβ6 Integrin-HER2 crosstalk to control breast cancer invasion and drug resistance

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer

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