ERBB2 Target Analysis Report Summary
About the Target
Based on the given context information, here are some key viewpoints regarding ERBB2 (HER2):
ERBB2 is a target for therapeutic interventions in the brain-specific drug resistance mechanisms associated with breast cancer brain metastases (BCBMs) [1].
In BCBMs, the blood-tumor barrier (BTB) becomes more permeable, allowing drugs like trastuzumab to penetrate the brain parenchyma. However, inhibition of HER2 alone is counteracted by brain-specific resistance mechanisms [1].
Resistance to PI3K inhibition in BCBMs is mediated by increased HER3 activation through the expression of neuregulin-HER3 axis, indicating that targeting both HER2 and HER3 shows promising efficacy [1].
ERBB2 amplification is shared among different subtypes of ERBB2-positive breast cancer (cHER2+ BC), but each subtype has a different mutational landscape. For example, luminal A/cHER2+ BC is expected to have mutational activation of PI3K signaling, while basal/cHER2+ and claudin-low/cHER2+ subtypes have mutations in TP53 and genomic alterations in PTEN [2].
Different molecular subtypes of cHER2+ BC have two different types of cancer stem cells (CSCs): a proliferative, epithelial-like state characterized by ALDH expression, and a quiescent, invasive, mesenchymal-like state characterized by CD44+CD24-/low expression [2].
Intratumoral cell heterogeneity significantly increases in the spectrum of luminal-to-basal subtypes, which explains how genetic and epigenetic heterogeneity can coalesce at the CSC level, affecting tumor evolution and clinical progression in individual tumors of each cHER2+ molecular subtype [2].
FKA counteracts HER2-mediated apoptosis resistance and functions as a selective G2 abrogator in HER2-overexpressing breast cancer cells [3].
Activation of the HER2-related pathway is higher in clinically HER2-positive/HER2-Enriched tumors compared to clinically HER2-positive/non-HER2-Enriched tumors [4].
Lapatinib, a dual reversible TKI, blocks HER2 signaling by competing with ATP, preventing auto phosphorylation, and blocking downstream MAPK/Erk1/2 and PI3K/AKT pathways [5].
Overall, the provided context information highlights the importance of targeting HER2 in breast cancer treatment, particularly in the context of brain metastases, different molecular subtypes, and resistance mechanisms. Different therapeutic strategies, including combination treatments and targeting downstream pathways, are being explored to address the challenges associated with HER2-positive breast cancer.
Based on the provided context information, the following viewpoints can be summarized regarding ERBB2 (also known as HER2) and its role in breast cancer:
ERBB2 is a member of the human epidermal growth factor receptor family and plays a crucial role in breast cancer [7].
New drugs have been approved for the treatment of breast cancer, targeting HER2, CDK 4/6, immunotherapy, PIK3CA, and PARP [6].
Trastuzumab (Herceptin) and lapatinib are examples of drugs that target HER2 and inhibit its signaling [7].
Resistance to anti-HER2 therapy can occur due to factors such as constitutive active p95HER2 fragment, activation of other signaling pathways, and rapid recycling of HER2-T-DM1 [8].
Mutations in p53 (mutp53) enhance ErbB2 signaling and potentiate HSF1 activity, leading to upregulation of Hsp90 clients, including mutp53 [9].
Inhibition of ErbB2 by lapatinib can lead to the inhibition of HSF1 transcriptional function, decline in Hsp90 levels, and subsequent degradation of mutp53 and MDM2 [9].
RNF40-driven H2B monoubiquitination is crucial for the activation of the RHO/ROCK/LIMK pathway and proper actin polymerization in HER2-positive breast cancer cells [10].
Loss of RNF40 impairs the trans-histone crosstalk of H2Bub1-H3K4me3, resulting in the downregulation of critical modulators of actin dynamics and reduced pro-survival signaling [10].
These viewpoints highlight the significance of HER2 in breast cancer, the mechanisms of targeted therapies, resistance mechanisms, and the interplay between HER2 signaling and other molecular pathways.
Figure [1]
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Note: If you are interested in the full version of this target analysis report, or if you'd like to learn how our AI-powered BDE-Chem can design therapeutic molecules to interact with the ERBB2 target at a cost 90% lower than traditional approaches, please feel free to contact us at BD@silexon.ai.
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