Valproic acid increased the efficacy of EGFR TKIs on EGFR/TP53 co-mutated lung cancers and downregulated mutant-p53 levels.

The TP53 tumor suppressor is the most frequently mutated gene in human cancers. For p53-targeted therapy, one of the strategies was targeting mutant p53 for degradation. In EGFR-mutated lung cancer patients, concurrent TP53 mutation was associated with faster resistance to EGFR-TKIs. In this study, we discovered that valproic acid (VPA), a widely prescribed antiseizure medication, had a synergic effect on sensitive as well as acquired resistant lung cancers with EGFR/TP53 co-mutation in combination with EGFR-TKIs. In both in vitro and in vivo models, VPA greatly improved the efficacy of EGFR-TKIs, including forestalling the occurrence of acquired resistance and increasing the sensitivity to EGFR-TKIs. Mechanistically, VPA dramatically promoted degradation of mutant p53 in both sensitive and acquired resistant cells while inhibited mutant TP53 mRNA transcription only in sensitive cells. Together, this study suggested that VPA combination treatment could have beneficial effects on EGFR-mutant lung cancers with concurrent p53 mutation in both early and late stages, expanding the potential clinical applications for VPA.

TGFß1/integrin ß3 positive feedback loop contributes to acquired EGFR TKI resistance in EGFR-mutant lung cancer.

Inevitable emergence of acquired resistance to EGFR TKIs including third-generation TKI osimertinib limits their long-term efficacy in treating EGFR-mutant lung cancer. A fuller investigation of novel molecular mechanisms underlying acquired resistance is essential to develop efficacious therapeutic strategies. Consequently, we have identified a novel TGFß1/integrin ß3 loop that contributes to the occurrence of EGFR TKI-acquired resistance. EGFR TKIs dramatically and sustainably increased the expression of both TGFß1 and integrin ß3 in in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to EGFR TKIs. Previously, we reported that integrin ß3 expression was partially induced by TGFß1 in these models. Moreover, elevated TGFß1 in these models was secreted mostly from lung cancer cells. Mechanistically, TGFß1 was induced and activated by overexpressed integrin ß3, forming a positive feedback loop. More importantly, the interruption of TGFß1/integrin ß3 positive feedback loop was shown to dramatically delay the occurrence of acquired resistance and greatly improve the efficacy of EGFR TKI in treating EGFR-mutant lung cancer. Taken together, our study first demonstrated the TGFß1/integrin ß3 loop a new mechanism and target for acquired EGFR TKI resistance in EGFR-mutant lung cancer.