Abstract
Introduction: The resistance of EGFR-TKIs is one of the most critical problem of lung cancer treatment. Hippo effector YAP is involved in EGFR-TKI resistance and PD-L1 transcription in lung cancer. Autophagy of cancer cell has very crucial role in critical contexts such as chemotherapy, radiation, and nutrient deprivation in lung cancer.
Result: This study assessed the role of autophagic key factor of p62 in high YAP expression gefitinib-resistance lung adenocarcinoma. The expression levels of LC-II were markedly increased and expression levels of p62 were decreased when EGFR-TKI-resistant cells were treated with EGFR-TKI. That means that EGFR-TKI resistant cells activate autophagic flux to survive in the treatment of EGFR-TKI. When we knocked down the YAP by siRNA in this context, the expression levels and mRNA of p62 were more decreased. To check whether the effect is hyperactivation of autophagic flux, we treated the cells with chloroquine to block the autophagic flux. The results showed that p62 levels were still decreased. It means that YAP decreased the expression of p62 rather than increasing autophagic degradation of p62. We checked the synergistic effect of EGFR-TKI and YAP knock down. The proliferation of the EGFR-TKI resistant cells was significantly decreased with EGFR-TKI and YAP knock simultaneously.
Conclusion: Taken together, our findings uncover a significant regulatory axis for autophagic key factor p62 by Hippo effector YAP in EGFR-TKI resistant lung adenocarcinoma. Targeting the autophagy by YAP could provide an effective therapeutic strategy for intractable lung cancer such as EGFR-TKI-resistant lung adenocarcinoma.
Footnotes
Cite this article as: European Respiratory Journal 2019; 54: Suppl. 63, PA4685.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2019