Novel Camptothecin Derivative 9c with Enhanced Antitumor Activity via NSA2-EGFR-P53 Signaling Pathway

Therapeutic challenges persist in the management of non-small cell lung cancer (NSCLC) in oncology. Camptothecins have demonstrated as crucial agents in tumor therapy; however, their efficacy is significantly hindered by adverse effects and drug resistance. Herein, we present a novel camptothecin derivative named 9c, which exhibits impressive anti-NSCLC potency surpassing the widely recognized camptothecin analog FL118 through a novel mechanism. Our findings demonstrated that 9c effectively inhibited tumor malignancy through cell cycle arrest and apoptosis induction with the transcriptional downregulation of anti-apoptotic genes including survivin, Mcl-1, Bcl-2, and XIAP. Mechanistically, 9c induced a wild-type p53 expression by destabilizing the NSA2-EGFR axis, thus delaying the cell cycle progression and ultimately triggering apoptosis. 9c significantly inhibited the growth of the NSCLC xenograft in vivo without observed side toxicity. Importantly, it complemented the therapeutic advantages of the novel drug AMG510 for addressing KRAS-mutant NSCLC. Collectively, these findings position 9c as a promising candidate with innovative approaches to combat NSCLC.