ZNF217 promotes receptor tyrosine kinase plasticity and AXL-ERK dependency in ovarian cancer
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,…
ZNF217, a potent oncogene, plays a significant role in promoting ovarian cancer progression and therapeutic resistance. Researchers have discovered that high levels of ZNF217 in ovarian cancer cells lead to increased expression of certain receptor tyrosine kinases, particularly AXL, which activates the MAPK signaling pathway. This, in turn, results in the rewiring of downstream signaling, causing an ERK-dominant state that sustains cell survival despite the presence of ERBB2 inhibitors.
The study further reveals that targeting the AXL-ERK axis can reduce cell viability and metastatic potential in vitro, as well as suppress tumor burden and prolong survival in ovarian cancer xenograft models. These findings suggest that ZNF217 establishes signaling plasticity, making it a crucial determinant of chemoresistance in ovarian tumors.
Consequently, targeting AXL and ERK signaling could be a promising strategy for treating ZNF217-high ovarian cancers.
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