biostudies-literatureSubramaniyan BNational Institutes of Health102629https://www.ebi.ac.uk/biostudies/studies/S-EPMC12719973biostudies-literatureUnknown63Mutations in nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2) occur in 10-22 % of esophageal squamous cell carcinoma (ESCC) cases and result in NRF2 activation, promoting tumor progression, and therapeutic resistance. Although previous studies suggested a link between NRF2 and kinases, specific kinases responsive to NRF2 activation remain to be fully identified. Using protein phosphorylation profiling and kinase activity profiling, we identified phosphatidylinositol 3-kinase (PI3K) pathway as a downstream effector in NRF2^W24C-KYSE70 cells compared to isogenic NRF2^null-KYSE70 cells. AREG, pEGFR, PIK3CA, pAKT, p-S6, and p-PTEN were downregulated in NRF2 deficient cells. Notably, NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors. Co-trTranslational oncologyThe PI3K pathway is a downstream effector of NRF2 activation in the esophagus.PMC12719973AA030026R01 CA244236Xiong ZLi YBui-Linh CSubramaniyan BSpitz FChen XPaiboonrungruang CfalseThe PI3K pathway is a downstream effector of NRF2 activation in the esophagus.Mutations in nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2) occur in 10-22 % of esophageal squamous cell carcinoma (ESCC) cases and result in NRF2 activation, promoting tumor progression, and therapeutic resistance. Although previous studies suggested a link between NRF2 and kinases, specific kinases responsive to NRF2 activation remain to be fully identified. Using protein phosphorylation profiling and kinase activity profiling, we identified phosphatidylinositol 3-kinase (PI3K) pathway as a downstream effector in NRF2^W24C-KYSE70 cells compared to isogenic NRF2^null-KYSE70 cells. AREG, pEGFR, PIK3CA, pAKT, p-S6, and p-PTEN were downregulated in NRF2 deficient cells. Notably, NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors. Co-tr2026-01-01T00:00:00Z2026 Jan2026-06-09T04:57:31.434Z2026-06-09T03:07:35.494ZS-EPMC127199734134405710.1016/j.tranon.2025.102629