Internal enhancement of DNA damage by a novel bispecific antibody ‐drug conjugate‐like therapeutics via blockage of mTOR and PD‐L1 signal pathways in pancreatic cancer

DTLP showed bispecific binding activities to EGFR/HER ‐2 in vitro and in vivo. DTLL showed potent anti‐pancreatic cancer efficacy in CDX and PDX mouse models of human pancreatic cancer 3. DTLL had an antineoplastic effect by inhibited AKT/mTOR and PD‐1/PD‐L1 signal pathways in human pancreatic cancer. AbstractPancreatic ductal adenocarcinoma (PDAC) is a refractory malignant tumor with poor prognosis, limited chemotherapeutic efficacy, and only about 5% of 5 ‐year survival rate. We generated a dual‐targeting ligand‐based lidamycin (DTLL) to investigate its efficacy against pancreatic cancer after preparing its precursor, DTLP. DTLP was shown specifically binding to EGFR and HER2 on cell surface, followed by endocytosis into cytoplasm of pancreatic cancer cells. DTLL significantly promoted apoptosis and cell cycle arrest at G2/M stages and inhibited cell proliferation. Pancreatic tumors of either MIA‐paca‐2 cell line‐derived (CDX) or patient‐derived xenograft (PDX) mouse models were significantly regressed in response to DTLL. It sugg ested that DTLL might be a highly potent bispecific antibody‐drug conjugate (ADC)‐like agent for pancreatic cancer therapy. LDM is known to function as an antitumor cytotoxic agent by its induction of DNA damage in cancer cells, therefore, DTLL, as its derivative, also showed similar cytotoxicit y. However, we found that DTLL might reverse the AKT/mTOR feedback activation induced by LDM at the first time. The results from...
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research