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

Monique B. Nilsson, Yan Yang, Simon Heeke, Sonia A. Patel, Alissa Poteete, Hibiki Udagawa, Yasir Y. Elamin, Cesar A. Moran, Yukie Kashima, Thiruvengadam Arumugam, Xiaoxing Yu, Xiaoyang Ren, Lixia Diao, Li Shen, Qi Wang, Minying Zhang, Jacqulyne P. Robichaux, Chunhua Shi, Allyson N. Pfeil, Hai TranDon L. Gibbons, Jason Bock, Jing Wang, John D. Minna, Susumu S. Kobayashi, Xiuning Le, John V. Heymach

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)340-355.e6
JournalCancer cell
Volume41
Issue number2
DOIs
StatePublished - Feb 13 2023

Keywords

  • CD70
  • EGFR
  • NSCLC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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