Co-targeting EGFR and SUCLG2 disrupts a nuclear transcriptional program driving neuroendocrine differentiation and TKI resistance in castration-resistant prostate cancer.

Neuroendocrine prostate cancer (NEPC) is a lethal, treatment-resistant subtype that arises through lineage transdifferentiation from castration-resistant prostate cancer (CRPC) under selective pressure from androgen deprivation therapy. Although EGFR tyrosine kinase inhibitors (TKIs) represent a rational therapeutic strategy, their clinical efficacy remains limited, and the underlying resistance mechanisms are poorly defined. Through integrated molecular and functional analyses, we identified the mitochondrial succinyl-CoA ligase subunit SUCLG2 as a critical driver of neuroendocrine differentiation and EGFR-TKI resistance. EGF stimulation induced SUCLG2 nuclear translocation, where it formed a complex with phosphorylated EGFR and co-activated VEGFA transcription through co-occupancy of the VEGFA promoter to drive neuroendocrine gene programs. SUCLG2 overexpression conferred erlotinib resistance in vitro, whereas its depletion restored TKI sensitivity and impaired xenograft tumor growth, effects that were rescued by VEGFA reconstitution. Through in silico drug screening, we identified phenethyl isothiocyanate (PEITC) as a compound that reverses the SUCLG2-associated transcriptional signature and synergized with erlotinib to suppress patient-derived NEPC organoid growth and reduce xenograft tumor burden in vivo. In clinical specimens from CRPC patients and NEPC patient-derived xenografts, progressive nuclear co-accumulation of SUCLG2 and EGFR alongside elevated VEGFA expression correlated with disease advancement. Collectively, these findings define a non-canonical nuclear SUCLG2/EGFR/VEGFA signaling axis that mediates NEPC progression and therapeutic resistance, providing mechanistic rationale for combined SUCLG2 and EGFR inhibition as a strategy to overcome treatment resistance in this lethal malignancy.