Targeting CD47 to improve osimertinib efficacy in EGFR mutant NSCLC

Frontiers JournalsMay 28 2024

NSCLC is the leading cause of cancer deaths globally, with EGFR mutations being a common feature in these cancers. Osimertinib has shown significant improvements in progression-free survival for patients with EGFR mutations. However, the median progression-free survival with osimertinib is still less than 2 years, indicating a need for combination therapies to enhance its efficacy.

CD47 is a transmembrane protein that acts as a "don't eat me" signal to macrophages, preventing phagocytosis of cancer cells. Many cancers upregulate CD47 to evade immune surveillance. The study found that osimertinib treatment upregulated CD47 expression in EGFR mutant cancer cells, suggesting a potential strategy to improve osimertinib's efficacy by blocking CD47.

Wei-Bang Yu et al., at State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, China, conducted a study that focused on the role of CD47 in non-small cell lung cancer (NSCLC) and its interaction with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI).

The study used various reagents, cell lines, and animal models to investigate the effects of osimertinib and anti-CD47 antibody on cancer cells. Techniques such as flow cytometry, Western blot, and quantitative real-time PCR were employed to measure CD47 expression and macrophage infiltration.
Osimertinib induced higher CD47 expression in certain lung cancer cells, which was found to be EGFR-dependent. The study showed that blocking CD47 with an anti-CD47 antibody (B6H12) enhanced the anticancer effect of osimertinib both in vitro and in vivo. Osimertinib also induced stronger antibody-dependent cellular phagocytosis (ADCP) of anti-CD47 antibody in lung cancer cells. The combination of osimertinib and anti-CD47 antibody led to a significant increase in phagocytosis and a better anticancer effect in a mouse xenograft model.

The study suggests that combining osimertinib with CD47 blockade could be a promising strategy to improve outcomes in EGFR mutant NSCLC. The findings also indicate that CD47 upregulation might play a role in resistance to osimertinib, although further research is needed to confirm this.

The research found that osimertinib upregulates CD47 expression via the NF-κB pathway and that the combination of osimertinib with an anti-CD47 antibody significantly promotes phagocytosis and enhances the anticancer effect, offering a potential new combination strategy for EGFR mutant NSCLC.
This research provides valuable insights into the potential for immunotherapy combined with targeted therapy in the treatment of NSCLC, highlighting the importance of understanding the complex interactions between cancer cells and the immune system.