E2A selectively regulates TGF-β-induced apoptosis in KRAS-mutant non-small cell lung cancer.

Transforming growth factor-β (TGF-β) regulates epithelial homeostasis by inducing growth arrest and apoptosis during early carcinogenesis; however, these tumor-suppressive functions are frequently lost in advanced nonsmall cell lung cancer (NSCLC) despite intact signaling. We identify the transcription factor E2A as a critical mediator of resistance to TGF-β-induced apoptosis in mutant KRAS-driven NSCLC. TGF-β induces E2A expression in a SMAD3-dependent manner in NSCLC cells harboring mutant KRAS, but not in those with wild-type KRAS. Silencing E2A restores TGF-β-induced apoptosis in mutant KRAS cell lines without affecting epithelial-mesenchymal transition. E2A depletion promotes mitochondrial apoptosis through mitochondrial outer membrane permeabilization, caspase-3 activation, and regulation of BCL-2 family and inhibitor-of-apoptosis proteins. In contrast, wild-type KRAS NSCLC cells fail to upregulate E2A in response to TGF-β and remain resistant to apoptosis following E2A silencing. Knockdown of mutant KRAS abrogates the pro-apoptotic effects of E2A silencing, establishing KRAS dependency. E2A silencing enhances radiation-induced growth inhibition, likely through increased sensitivity to TGF-β signaling. E2A is overexpressed in lung adenocarcinoma and is significantly elevated in tumors harboring mutant KRAS. These findings identify E2A as a context-specific suppressor of TGF-β-mediated apoptosis and a potential therapeutic target in mutant KRAS NSCLC.