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

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• Non-small cell lung cancer (NSCLC) with EGFR mutations often develops resistance to tyrosine kinase inhibitors (TKIs).
• Epithelial-to-mesenchymal transition (EMT) is a key mechanism driving acquired resistance to EGFR TKIs.
• Effective therapeutic strategies are needed to overcome this resistance.

Purpose of the Study:

• To identify novel cell surface targets for antibody-based or adoptive cell therapy in EGFR TKI-resistant NSCLC.
• To investigate the role of CD70 in EMT-associated resistance to EGFR TKIs.
• To evaluate the therapeutic potential of targeting CD70 in preclinical models.

Main Methods:

• Analysis of cell surface protein expression in EGFR TKI-resistant NSCLC models with EMT.
• Investigation of CD70 expression dynamics during resistance evolution and in drug-tolerant persister cells (DTPCs).
• Assessment of anti-CD70 antibody-drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T and CAR NK cells in vitro and in vivo.

Main Results:

• CD70 is highly upregulated in NSCLC cells exhibiting EMT-associated resistance to EGFR TKIs.
• CD70 upregulation is an early event in resistance development and is present in DTPCs.
• Stimulation of CD70 activates signaling pathways implicated in acquired TKI resistance.
• Anti-CD70 ADCs and CD70-targeting CAR T/NK cells demonstrate potent anti-tumor activity against resistant cells and DTPCs.

Conclusions:

• CD70 is a validated therapeutic target for EGFR mutant NSCLC with acquired TKI resistance.
• Targeting CD70 offers a promising strategy for overcoming EMT-driven resistance.
• CD70-based immunotherapies warrant further clinical investigation for this patient population.