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

• Published in: Cancer cell Vol. 41; no. 2; pp. 340 - 355.e6
• Main Authors: Nilsson, Monique B., Yang, Yan, Heeke, Simon, Patel, Sonia A., Poteete, Alissa, Udagawa, Hibiki, Elamin, Yasir Y., Moran, Cesar A., Kashima, Yukie, Arumugam, Thiruvengadam, Yu, Xiaoxing, Ren, Xiaoyang, Diao, Lixia, Shen, Li, Wang, Qi, Zhang, Minying, Robichaux, Jacqulyne P., Shi, Chunhua, Pfeil, Allyson N., Tran, Hai, Gibbons, Don L., Bock, Jason, Wang, Jing, Minna, John D., Kobayashi, Susumu S., Le, Xiuning, Heymach, John V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.02.2023
• Subjects: Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; CD27 Ligand - genetics; CD70; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; EGFR; Epithelial-Mesenchymal Transition - genetics; ErbB Receptors - metabolism; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Mutation; NSCLC; Tyrosine Kinase Inhibitors - therapeutic use; NSCLC; CD70; EGFR
• ISSN: 1535-6108; 1878-3686; 1878-3686
• 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. [Display omitted] •CD70 is upregulated on EGFR mutant NSCLC cells that have undergone EMT•In EGFR inhibitor-resistant cells, CD70 regulates cell survival and invasiveness•CD70 upregulation occurs in drug-tolerant persister cells (DTPCs)•Drug-resistant CD70+ tumors can be targeted with CD70-ADCs, CAR Ts, and NK-CARs Nilsson et al. show that CD70 is highly upregulated in non-small cell lung cancer (NSCLC) tumors with acquired EGFR tyrosine kinase inhibitor (TKI) resistance that occurs independent of MET or secondary EGFR mutations. Anti-CD70 antibody drug conjugates and CD70-targeting CAR T and CAR NK cells have activity against resistant cells and drug-tolerant persister cells.