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Preprint WatchModerateSeptember 15th, 2026

ZNF217 promotes receptor tyrosine kinase plasticity and AXL-ERK dependency in ovarian cancer

Pandya MJ, Hoffman J, Padmanabhan A.

ZNF217 overexpression raises ERBB2 levels yet confers resistance to multiple ERBB2 inhibitors, because ZNF217 upregulates AXL and ERK1/2 and establishes an ERK-dominant signalling state that sustains survival despite ERBB2 blockade; targeting the AXL-ERK axis reduced viability and tumour burden in vitro and in xenografts.

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 ZNF217 overexpression raises ERBB2 levels in ovarian cancer cells while those same cells resist multiple ERBB2 inhibitors, and that resistance runs through AXL and an ERK-dominant signalling state rather than through the receptor itself. The claim that receptor abundance does not predict inhibitor sensitivity is the same disconnect already on file in the Claidex graph for this target. In poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch, an ERBB2 alteration selected the population and the drug still failed to deliver durable benefit, which was classified as a translational mismatch. In xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation, a HER2-directed immunostimulatory conjugate in HER2-expressing solid tumours was discontinued for portfolio reasons before that question was settled. Two prior ERBB2 programmes and this preprint point at the same design risk: enrolling on ERBB2 expression or mutation status assumes the receptor is the node that matters, and the preprint offers a specific mechanism by which it is not. Any new ERBB2-directed programme, and in particular any that proposes ERBB2 protein level as an enrichment biomarker, should pre-specify how it will measure AXL and ERK pathway state at baseline.

Abstract excerpt

ZNF217 is a potent oncogene that drives ovarian cancer progression and therapeutic resistance. We show that ZNF217 overexpression markedly increases ERBB2 levels in ovarian cancer cells, suggesting its potential as a biomarker to identify ovarian tumors that will respond to ERBB2-targeted therapeutics. Unexpectedly, ZNF217-high ovarian cancer cells exhibit resistance to multiple ERBB2 inhibitors, revealing a disconnect between receptor abundance and drug sensitivity. Mechanistically, ZNF217 drives chemoresistance by elevating the expression of several key receptor tyrosine kinases, most notably AXL, that activates MAPK signaling. Further, ZNF217 also upregulates ERK1/2 levels in ovarian cancer cells. This induces rewiring of downstream signaling, promoting an ERK-dominant state that sustains survival despite ERBB2 inhibition. Therapeutic targeting of the AXL-ERK axis reduced cell viability and metastatic potential in vitro, while suppressing tumor burden and prolonging survival in xenograft models. Thus, by elevating the expression of several key signaling receptors and their downstream effectors in ovarian cancer cells, ZNF217 establishes signaling plasticity that defines a novel mechanism of chemoresistance. These findings identify ZNF217 as a key determinant of signaling state and drug response and provides rationale to evaluate targeting AXL and ERK signaling in ZNF217-high ovarian tumors.

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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.