TCCC-1 peptide-drug conjugate achieves 97% tumor suppression in NSCLC xenografts by degrading PI3K via CMA

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently hyperactivated in various cancers, driving tumor growth and fostering resistance to conventional treatments. Existing PI3K inhibitors often face significant challenges, including poor tumor selectivity, systemic toxicity, and the rapid development of acquired resistance, limiting their clinical utility. This research addresses these critical gaps by developing a targeted strategy that leverages chaperone-mediated autophagy (CMA), a highly selective lysosomal degradation mechanism, to precisely eliminate PI3K within tumor cells, aiming for enhanced efficacy and reduced side effects.

Researchers developed TCCC-1, a multifunctional peptide-drug conjugate (PDC) derived from Copanlisib, incorporating a KFERQ-like CMA-recognition motif, a tumor-homing peptide (Thx), and a cell-penetrating peptide (T2). In vitro studies evaluated TCCC-1's effects on PI3K degradation, pAkt signaling, apoptosis, and cell cycle arrest in non-small cell lung cancer (NSCLC) cells, including those resistant to Copanlisib. In vivo experiments utilized NCI-H460 xenograft models to assess TCCC-1's tumor suppression efficacy compared to Copanlisib, alongside systemic toxicity, organ damage, and metabolic disturbances.

In in vitro studies, TCCC-1 effectively induced PI3K degradation, significantly inhibited downstream pAkt signaling, and promoted apoptosis alongside G2/M cell cycle arrest in NSCLC cells, including those resistant to Copanlisib. This demonstrated its potent cellular activity and ability to overcome drug resistance. In in vivo experiments using NCI-H460 xenograft models, TCCC-1 exhibited remarkable anti-tumor efficacy.

TCCC-1 achieved up to 97.0% tumor suppression at high doses, significantly surpassing the efficacy observed with Copanlisib. Crucially, this potent anti-tumor effect was achieved without causing significant systemic toxicity, organ damage, or metabolic disturbances such as hyperglycemia, indicating a favorable safety profile compared to conventional inhibitors.