Command Palette

Search for a command to run...

Preprint WatchModerateAugust 26th, 2026

Membrane PI(4,5)P2 and ErbB2 abundance regulate ErbB receptor signaling through receptor oligomerization and activation

Abe, M.; Yanagawa, M.; Sako, Y.

ErbB2 abundance and membrane PI(4,5)P2 govern which ErbB heterodimers form and how strongly they signal, with ErbB2 preferentially promoting ErbB4 rather than ErbB1 oligomerization and the ErbB2 kinase module showing weak PI(4,5)P2 dependence.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that ErbB2 abundance and membrane PI(4,5)P2 levels determine which ErbB heterodimers form and how strongly the resulting complexes signal, with ErbB2 driving ErbB4 oligomerization in preference to ErbB1. Claidex holds two ERBB2 failures, poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch, where a HER2 exon 20 inhibitor did not reproduce its preclinical profile in patients, and xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation, a HER2-directed conjugate discontinued for portfolio reasons. The common thread is that HER2 was treated as a single addressable node and stratification used HER2 expression or mutation status alone. If receptor abundance and lipid context decide the dimer composition that actually carries signal, then two tumours with identical HER2 status can present different pharmacology, and expression-only enrichment will keep producing heterogeneous response.

Abstract excerpt

Because ErbB receptors play distinct roles in regulating diverse cellular functions, the mechanisms governing ErbB receptor activation are likely to be more diverse than previously recognized. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] positively regulates ErbB1 kinase activity, but the role of PI(4,5)P2 in regulating other ErbB family members in living cells remains poorly understood. We show that disruption of PI(4,5)P2 binding enhances ErbB4 oligomerization and kinase activity while reducing both processes in ErbB1. Analysis of chimeric receptors identified the juxtamembrane (JM) regions of ErbB1 and ErbB4 as key determinants of their distinct responses to PI(4,5)P2 during receptor oligomerization and kinase activation. Furthermore, the JM-kinase module of ErbB1 is more active in the presence of PI(4,5)P2, whereas that of ErbB4 is activated by the disruption of PI(4,5)P2 binding. In contrast, the JM-kinase module of ErbB2 exhibits weak dependence on PI(4,5)P2. ErbB2 preferentially promotes ErbB4 oligomerization over ErbB1 oligomerization, thereby enhancing ErbB4 activation. Collectively, these findings identify plasma membrane PI(4,5)P2 availability and ErbB2 abundance as two factors that jointly govern ErbB receptor oligomerization and activation.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.