Journal
CANCER CELL
Volume 41, Issue 2, Pages 340-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2023.01.007
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This study identified CD70 as a significantly upregulated cell surface protein in non-small cell lung cancer (NSCLC) patients with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) through epithelial-to-mesenchymal transition (EMT). CD70 promotes cell survival and invasiveness by reactivating signal transduction pathways associated with acquired TKI resistance. Anti-CD70 antibody drug conjugates (ADCs) as well as CD70-targeting chimeric antigen receptor (CAR) T cells and CAR NK cells showed strong activity against EGFR TKI-resistant cells. These findings suggest that CD70 could serve as a therapeutic target for EGFR mutant tumors with acquired TKI resistance.
Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upre-gulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. Anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. These re-sults identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation.
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