Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment

CUB domain‐containing protein 1 (CDCP1) contributes to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance by regulating EGFR signaling pathways and is a potential target in lung cancer treatment. This study aims to identify a CDCP1 reducer that synergistically improves TKI treatment. Utilizing a high‐throughput drug screening system, a phytoestrogen 8‐isopentenylnaringenin (8PN) was identified. Upon 8PN treatment, CDCP1 protein levels and malignant features were reduced. 8PN exposure caused the accumulation of lung cancer cells in G0/G1 phase and increased the proportion of senescent cells. In EGFR TKI‐resistant lung cancer cells, the combination of 8PN and TKI synergistically reduced cell malignance, inhibited downstream EGFR pathway signaling, and exerted additive effects on cell death. Moreover, combination therapy effectively reduced tumor growth and enhanced tumor necrosis in tumor xenograft mice models. Mechanistically, 8PN increased interleukin (IL)6 and IL8 expression, induced neutrophil infiltration, and enhanced neutrophil‐mediated cytotoxicity to attenuate lung cancer cell growth. In conclusion, 8PN enhances the anticancer efficacy of EGFR TKI on lung cancer and triggers neutrophil‐dependent necrosis, highlighting the potential to overcome TKI resistance in lung cancer patients who have EGFR mutation. CUB domain‐containing protein 1 (CDCP1) contributes to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in lung cancer treatment. 8‐isopentenylnaringenin (8PN) was identified as a CDCP1 reducer to suppress CDCP1 proteins via lysosomal degradation and reduced lung cancer progression. The combination of 8PN and EGFR TKIs showed a synergistic anticancer effect. Mechanically, 8PN increases interleukin (IL)6 and IL8 expressions to recruit neutrophils, leading to reactive oxygen species production for tumor necrosis.