An auristatin-based peptide-drug conjugate targeting Kita-Kyushu lung cancer antigen 1 for precision chemoradiotherapy in gastric cancer

  • Eur J Med Chem. 2022 Nov 5:241:114617. doi: 10.1016/j.ejmech.2022.114617.
Xiaotong Chen  1 ,  Fangcen Liu  2 ,  Xiaoxiao Yu  1 ,  Lin Li  2 ,  Jiayao Yan  1 ,  Xinjie Chen  1 ,  Qin Liu  3 ,  Baorui Liu  4
Affiliations
  • 1. The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
  • 2. Department of Pathology of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China, Nanjing, 210008, China.
  • 3. The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China. Electronic address: [email protected].
  • 4. The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China. Electronic address: [email protected].
PMID: 35932567 DOI: 10.1016/j.ejmech.2022.114617
Abstract

Gastric Cancer is a worldwide health problem. Chemotherapy and radiotherapy are of great importance in the management of advanced gastric Cancer. However, their therapeutic efficacy is limited by off-target side effects. Peptide-drug conjugates (PDCs) are a novel strategy for tumor-targeted drug delivery to overcome the existing drug resistance mechanisms and improve antitumor effects. Kita-Kyushu lung Cancer antigen 1 (KK-LC-1) is exclusively expressed in several types of Cancer including gastric Cancer, representing a promising target for drug delivery. Here, we suggested KK-LC-1 as a potential target for PDC design for the first time and reported the first KK-LC-1-targeting PDC product 1131-MMAE, which is composed of a KK-LC-1-targeting peptide and an antimitotic drug conjugated by an enzymatically Cleavable Linker. We observed that 1131-MMAE could be efficiently endocytosed by KK-LC-1 positive gastric Cancer cells for subsequent drug release and arrest the cell cycle at the most radiosensitive G2/M phase. We demonstrated that 1131-MMAE could significantly delay tumor growth with reduced toxicity than free drugs as a monotherapy. We further confirmed that 1131-MMAE was also a potent radiosensitizer. 1131-MMAE could selectively enhance the radiation response of KK-LC-1 positive tumor cells and achieve improved tumor control when combined with low-dose radiation. Overall, our study proposed an optimized therapeutic regimen for precision chemoradiotherapy, which has translational potential in multiple types of Cancer.

Keywords
Gastric cancer; Kita-kyushu lung cancer antigen 1; Peptide-drug conjugate; Precision chemoradiotherapy; Targeted drug delivery.