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We generated a dual\u2010targeting ligand\u2010based 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\u2010paca\u20102 cell line\u2010derived (CDX) or patient\u2010derived xenograft (PDX) mouse models were significantly regressed in response to DTLL. It suggested that DTLL might be a highly potent bispecific antibody\u2010drug conjugate (ADC)\u2010like 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 cytotoxicity. However, we found that DTLL might reverse the AKT\/mTOR feedback activation induced by LDM at the first time. The results from both in vitro and in vivo experiments suggested that DTLL enhanced DNA damage via EGFR\/HER2\u2010dependent blockage of PI3K\/AKT\/mTOR and PD\u2010L1 signaling pathways in cancer cells, leading to the inhibition of cell proliferation and immunosurveillance escape from pancreatic tumor. Our studies on DTLL functional characterization revealed its novel mechanisms on internal enhancement of DNA damage and implied that DTLL might provide a promising targeted therapeutic strategy for pancreatic cancer.<\/jats:p>","DOI":"10.1002\/cam4.1974","type":"journal-article","created":{"date-parts":[[2019,1,25]],"date-time":"2019-01-25T12:11:42Z","timestamp":1548418302000},"page":"643-655","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Internal enhancement of DNA damage by a novel bispecific antibody\u2010drug conjugate\u2010like therapeutics via blockage of mTOR and PD\u2010L1 signal pathways in pancreatic cancer"],"prefix":"10.1002","volume":"8","author":[{"given":"Rui","family":"Cao","sequence":"first","affiliation":[{"name":"Key Laboratory of Antibiotic Bioengineering of National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology (IMB) Chinese Academy of Medical Sciences 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