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Preprint WatchModerateOctober 27th, 2026

The epidermal growth factor (EGF) receptor family network in cardiac hypertrophy and heart failure

Fuller, S. J.; Cooper, S. T.; Cull, J. J.; Adamczyk, N.; Tapsell, C.; Pokora, R.; Spilletts, J.; Dash, P. R.; Sugden, P. H.; Clerk, A.

Within the EGFR receptor family network, NRG1 signalling through ERBB2 and ERBB4 is cardioprotective while other EGFR ligands are implicated in cardiomyocyte hypertrophy, so ERBB2 pathway activity is a determinant of cardiac tolerance.

Moderate contradiction

2 prior failures

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

This preprint maps the EGF receptor family network in human heart failure and in rat cardiomyocyte hypertrophy, reporting that NRG1 acting through ERBB2 and ERBB4 is cardioprotective while other EGFR ligands are implicated in hypertrophy. Claidex holds two ERBB2 post-mortems, both in oncology. The entry poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch records a mismatch between exon 20 binding potency and the exposure patients tolerated. The entry xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation records a Phase 1 ERBB2 antibody-drug conjugate discontinued for strategic reasons. The overlap here is pathway biology rather than shared indication, and that distinction matters for how the flag should be read. If baseline ERBB2 signalling is cardioprotective, the therapeutic window for ERBB2-directed agents is set partly by cardiac tolerance and not by tumour selectivity alone, which is consistent with the exposure ceiling described in the poziotinib entry. The practical use of this preprint is in dose-finding and cardiac monitoring design for new ERBB2 agents.

Abstract excerpt

The epidermal growth factor receptor (EGFR) network comprises 4 receptors (EGFR, ERBB2, ERBB3, ERBB4) and multiple ligands (EGFR-Ls; for example, AREG/EGF/TGFA that bind to EGFR, EREG/HBEGF that bind to EGFR/ERBB3, and NRG1 that binds to ERBB3/4). NRG1 and ERBB2/ERBB4 are cardioprotective, whilst other EGFR-Ls are implicated in cardiomyocyte hypertrophy. We sought to understand the importance of this network in human heart failure and development of cardiac hypertrophy. By mining data from the Human Protein Atlas, we established that the EGFR family and EGFR-Ls are expressed in different cardiac cells. Furthermore, EGFR-L mRNAs were modulated in failing vs non-failing human hearts implicating them in end-stage disease. In rat cardiomyocytes, EGFR-Ls all activated extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt. However, NRG1 preferentially activated Akt whereas AREG/EREG/HBEGF/TGFA preferentially activated ERK1/2. EGF and NRG1 differentially regulated early gene expression with the response to NRG1 having a greater requirement for ERBB2. To determine if the network is involved in developing cardiac hypertrophy, mice were treated with angiotensin II (AngII) without/with afatinib (to inhibit all EGFR family members). Expression of EGFR-L mRNAs was modulated by AngII over 3-7d. At 7d, echocardiography and segmental strain analysis identified greater cardiac dysfunction in hearts from mice treated with afatinib/AngII compared with AngII alone, associated with inhibition of cardiomyocyte hypertrophy and enhanced cardiac fibrosis. In conclusion, the EGFR network plays an important role in cardiomyocyte and cardiac hypertrophy and is dysregulated in human failing hearts. Further insight into the network may enable identification of novel therapies for cardiac disorders.

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.