CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance

Cancer Cell. 2023 Feb 13;41(2):340-355.e6. doi: 10.1016/j.ccell.2023.01.007.


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 upregulated 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 results identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation.

Keywords: CD70; EGFR; NSCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD27 Ligand / genetics
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Mutation
  • Tyrosine Kinase Inhibitors* / therapeutic use


  • CD27 Ligand
  • CD70 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Tyrosine Kinase Inhibitors