Comprehensive review of natural products targeting lapatinib resistance-related pathways in breast cancer as future strategies to overcome lapatinib resistance.

BACKGROUND: Lapatinib (LAP) significantly improves outcomes in HER2-positive (HER2+) breast cancer, including trastuzumab-resistant p95HER2-expressing tumors. However, primary and acquired resistance remain unmet clinical challenges. Multiple studies have highlighted the promising role of natural products in breast cancer therapy. Given their ability to modulate multiple oncogenic signaling pathways, these compounds also represent potential therapeutic agents for overcoming LAP resistance. PURPOSE: In this review, we integrate current evidence on the molecular mechanisms underlying LAP resistance with the therapeutic potential of natural products to overcome these resistance pathways. STUDY DESIGN: We analyzed studies published between 2006 and 2026 investigating natural products in breast cancer, with a particular focus on their modulation of LAP resistance-associated molecular networks. RESULTS: A total of 194 preclinical studies and 34 clinical trial reports were included. Apoptosis (n = 64) and PI3K/AKT/mTOR signaling (n = 59) were the most frequently targeted mechanisms, followed by RAS/RAF/MEK/MAPK (n = 32), autophagy (n = 17), cell plasticity (n = 13), HER and FOXO signaling (n = 11 each), with fewer studies targeting Src, MET, IGF-1R, FGFR, PTEN, PP2A, and BRK pathways. CONCLUSION: This review highlights the potential of natural products to target the complex molecular networks underlying LAP resistance, although further validation in LAP-resistant models and dedicated clinical trials is required to confirm their therapeutic value.