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Abstract
SUMMARYEffective 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.
Highlights
The treatment of cancers by targeting their driving kinase oncogenes is a highly rational and validated treatment approach, producing profound remissions in the majority of patients with targetable kinase oncogene-driven cancers, replacing cytotoxic chemotherapies (Chapman et al, 2011; Kantarjian et al, 2002; Maemondo et al, 2010; Shaw et al, 2013)
HER3 is essential for tumorigenesis and functions in mediating drug resistance that becomes apparent when HER2 inhibitors are used to suppress HER2-HER3 signaling. This is because HER3 expression is highly dynamic and functionally linked with downstream negative feedback signaling, and the rapid compensatory upregulation of HER2-HER3 signaling following drug exposure allows for a 2-log increase in signaling output, presenting a stoichiometric barrier that has far remained outside the therapeutic index of all current pharmaceutical technologies, including bestin-class reversible and irreversible inhibitors acting at the active site of the HER2 kinase domain (KD) (Amin et al, 2010; Garrett et al, 2011; Sergina et al, 2007)
In the physiologic ligand-induced mode of signaling, the KDs of the HER family are activated through an asymmetric interaction wherein the C-lobe of an activator kinase interfaces with the N-lobe of a receiver kinase (Jura et al, 2009b; Kovacs et al, 2015; Qiu et al, 2008; Zhang et al, 2006)
Summary
The treatment of cancers by targeting their driving kinase oncogenes is a highly rational and validated treatment approach, producing profound remissions in the majority of patients with targetable kinase oncogene-driven cancers, replacing cytotoxic chemotherapies (Chapman et al, 2011; Kantarjian et al, 2002; Maemondo et al, 2010; Shaw et al, 2013). HER3 is essential for tumorigenesis and functions in mediating drug resistance that becomes apparent when HER2 inhibitors are used to suppress HER2-HER3 signaling This is because HER3 expression is highly dynamic and functionally linked with downstream negative feedback signaling, and the rapid compensatory upregulation of HER2-HER3 signaling following drug exposure allows for a 2-log increase in signaling output, presenting a stoichiometric barrier that has far remained outside the therapeutic index of all current pharmaceutical technologies, including bestin-class reversible and irreversible inhibitors acting at the active site of the HER2 kinase domain (KD) (Amin et al, 2010; Garrett et al, 2011; Sergina et al, 2007). This makes it much more challenging for functional targeting and is not suited for the standard pharmaceutical platforms for
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