Gracillin overcomes osimertinib resistance in NSCLC via dual inhibition of EGFR and Mcl-1.

The advent of molecularly targeted therapies has revolutionized the clinical management of non-small cell lung cancer (NSCLC), substantially expanding therapeutic options. Nevertheless, significant clinical challenges persist, including acquired resistance, treatment-related toxicities, and economic burdens, underscoring the need for novel therapeutic strategies. In this study, we identified a promising epidermal growth factor receptor (EGFR)-targeting natural product, Gracillin. Unlike osimertinib's selective profile, Gracillin possesses broad-spectrum efficacy against both EGFR-mutant (including Ex19del, L858R, and T790M variants) and wild-type (WT) NSCLC. Mechanistically, Gracillin-mediated EGFR inhibition suppresses Akt signaling, leading to GSK3β-dependent phosphorylation of Mcl-1 at Ser159. This post-translational modification promotes β-TRCP-mediated K48-linked polyubiquitination and degradation of Mcl-1, thereby reducing its protein levels and subsequently inducing apoptosis. In vitro, Gracillin reduced cell viability by up to 90% (IC₅₀ ≈ 1.4-2.78 µM) in both EGFR-mutant and WT NSCLC cell lines. Notably, in vivo studies corroborated these findings, with Gracillin demonstrating significant tumor growth inhibition of up to 60% in both osimertinib-sensitive and -resistant NSCLC models. The compound's unique ability to target diverse EGFR genotypes while overcoming TKI resistance suggests its potential as a therapeutic agent with a strong rationale for further clinical development.