A novel anticancer natural product SP09 selectively targets KRAS-mutant NSCLC through LKB1/AMPK/mTOR modulation:...

KRAS -mutant non-small cell lung cancer (NSCLC) remains a major therapeutic challenge due to the paucity of effective targeted agents. Although covalent KRAS^G12C inhibitorsi such as sotorasib and adagrasib have demonstrated clinical activity, pooled analyses indicate only modest response rates and short progression-free survival, with no effective options for non-G12C subtypes. This highlights the need for novel therapeutic strategies with broader efficacy and improved durability. We evaluated the antiproliferative effects of SP09, a novel benzoin-Schiff base derivative, in KRAS -mutant (A549, H460) and EGFR -mutant (PC9) NSCLC cells, as well as normal lung cells. Cell viability, colony formation, and cell cycle distribution were assessed, and the involvement of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling axis was examined by western blot. SP09 selectively inhibited the proliferation of KRAS -mutant NSCLC cells (IC 50 ≈ 29 µM) with minimal toxicity to normal lung cells. Treatment induced G2/M arrest via downregulation of cyclin B1 and upregulation of p21. Mechanistically, SP09 activated the LKB1/AMPK pathway and suppressed mTOR signaling, leading to inhibition of downstream effectors, including P70S6K, S6, and sterol regulatory element-binding protein 1 (SREBP1). SP09 exerts potent and selective antiproliferative effects in KRAS -mutant NSCLC through dual regulation of cell cycle and metabolic signaling pathways. Given the restricted efficacy and rapid resistance associated with current KRAS -targeted therapies, our data highlight SP09 as a promising candidate for further preclinical development with potential translational value in KRAS -driven NSCLC.