Reversal of acquired osimertinib resistance by YAP inhibition in lung cancer is associated with lipid metabolic reprogramming.

Abstract

Osimertinib (Osi), as the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated remarkable efficacy in the treatment of non-small cell lung cancer (NSCLC). However, recent studies have found that its acquired resistance severely limits its therapeutic effect. This study shows that YAP activation is associated with lipid metabolic reprogramming in Osi-acquired resistance, providing new insights into overcoming this clinical challenge. In H1975/OR cells, YAP phosphorylation was decreased and nuclear translocation was increased, indicating YAP activation. Inhibition or knockdown of YAP significantly re-stored Osi sensitivity. YAP upregulated the expression of sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FASN), and stearoyl-CoA desaturase (SCD1), and promoted the synthesis of triglycerides, cholesterol, and phospholipids. Lipidomics revealed that YAP inhibition reduced multiple phospholipids. Furthermore, inhibition of YAP downregulated the anti-apoptotic protein B-cell lymphoma 2 (BCL2) and enhanced Osi-induced apoptosis. This study firstly links YAP activation to lipid metabolic reprogramming and reveals its crucial role in Osi-acquired resistance. These findings not only deepen the understanding of the EGFR-TKI resistance mechanism but also provide a new therapeutic strategy for clinically overcoming Osi-acquired resistance. Targeting the phospholipid synthesis pathway mediated by YAP may effectively reverse the acquired resistance of NSCLC to Osi.