Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers
Marcia R Campbell1, Ana Ruiz-Saenz2, Elliott Peterson1
1Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Abstract:
Effective inactivation of the HER2-HER3 tumor driver has remained elusive because of the challenging attributes of the pseudokinase HER3. We report a structure-function study of constitutive HER2-HER3 signaling to identify opportunities for targeting. The allosteric activation of the HER2 kinase domain (KD) by the HER3 KD is required for tumorigenic signaling and can potentially be targeted by allosteric inhibitors. ATP binding within the catalytically inactive HER3 KD provides structural rigidity that is important for signaling, but this is mimicked, not opposed, by small molecule ATP analogs, reported here in a bosutinib-bound crystal structure. Mutational disruption of ATP binding and molecular dynamics simulation of the apo KD of HER3 identify a conformational coupling of the ATP pocket with a hydrophobic AP-2 pocket, analogous to EGFR, that is critical for tumorigenic signaling and feasible for targeting. The value of these potential target sites is confirmed in tumor growth assays using gene replacement techniques.
Insights
Targeting the HER2-HER3 tumor driver is difficult due to HER3’s pseudokinase nature. This study reveals a novel allosteric target site on HER3, offering new therapeutic strategies for HER2-HER3 driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Structural Biology
Background:
- The HER2-HER3 signaling pathway is a critical driver in various cancers, yet effective therapeutic targeting remains challenging.
- The pseudokinase HER3 presents unique structural attributes that complicate its inhibition.
- Constitutive HER2-HER3 signaling contributes to tumorigenesis, necessitating the identification of novel therapeutic targets.
Purpose of the Study:
- To conduct a structure-function analysis of constitutive HER2-HER3 signaling.
- To identify novel allosteric target sites on the HER3 pseudokinase domain for therapeutic intervention.
- To validate the identified target sites in preclinical cancer models.
Main Methods:
- Structure-function studies of HER2-HER3 signaling.
- X-ray crystallography of HER3 kinase domain (KD) bound to bosutinib.
- Site-directed mutagenesis to disrupt ATP binding in HER3 KD.
- Molecular dynamics simulations of apo HER3 KD.
- Tumor growth assays using gene replacement techniques.
Main Results:
- Allosteric activation of the HER2 kinase domain by the HER3 KD is essential for tumorigenic signaling and a potential target for allosteric inhibitors.
- ATP binding in the HER3 KD confers structural rigidity, but small molecule ATP analogs mimic, rather than oppose, this effect.
- A conformational coupling between the ATP pocket and a hydrophobic AP-2 pocket in the apo HER3 KD was identified, critical for signaling.
- Mutational disruption and molecular dynamics simulations confirmed the feasibility of targeting this newly identified site.
Conclusions:
- The study identifies a novel, druggable allosteric site within the HER3 pseudokinase domain.
- Targeting the conformational coupling between the ATP and AP-2 pockets in HER3 offers a promising strategy for inhibiting HER2-HER3 driven tumorigenesis.
- These findings pave the way for developing new therapeutics against cancers reliant on HER2-HER3 signaling.
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