52P - The dependence of TKI-resistant lung cancer cells on EGFR increases sensitivity to EGFR-CAR NK.

Background

Lung cancer's multiple resistance to tyrosine kinase inhibitors is inexorable and often unexplained in many NSLCs with EGFR mutations or other oncogenes and epigenetic changes. This suggests the need for new treatment strategies.

Methods

We generated second-generation CD28-costimulated EGFR-specific CAR constructs using lentiviral vectors to modify NK92 cells. We evaluated the utility of NK92 cells expressing a CAR-EGFR against TKI-resistant lung cancer cells at a low effector-to-target ratio to allow possible escape or evolution of select lung cancer cells. EGFR expression was analyzed by flow cytometry.

Results

We evaluated the utility of NK92 cells expressing a CAR-EGFR against TKI-resistant lung cancer cells. Our approach used a low effector-to-target ratio to allow possible escape or evolution of select lung cancer cells. We found that Gefitinib-resistant lung cancer cells HCC827GR6 and TKI-sensitive HCC827 are equally attacked by NK92 cells. However, TKI-resistant HCC827GR6 were more sensitive to EGFR-CAR NK cell attacks than parental HCC827. Predictably, EGFR-CAR NK cell attacks led to reduced EGFR expression in HCC827 and growth without increasing resistance to naïve NK92 attacks. However, the EGFR-CAR NK cell attack caused an increase in EGFR expression in gefitinib-resistant HCC827GR6 cells with a slight reduction in growth. This paradoxical increased EGFR protein expression suggests a positive selection of mutant EGFR, reducing their chance of escaping new EGFR-CAR NK cell attacks. Indeed, in co-culture experiments of TKI-sensitive and TKI-resistant cells, the latter were more efficiently eliminated, suggesting the preferential killing of TKI-resistant lung cancer cells by EGFR-CAR NK.

Conclusions

Our data indicate that TKI-resistant lung cancer cells, which evolved to depend on the expression of a mutated EGFR, are targeted more efficiently by EGFR-CAR NK cells than TKI-sensitive cells.

Legal entity responsible for the study

Sumei Chen and Youssef Jounaidi.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.