Page 20 - SDIR5 Abstract book 21 12 2021.

CANCER AND METABOLISM

Session: Cancer and metabolism
LECTURES

An antibody drug conjugate-like agent DTLL sensitizes gemcitabine efficacy in pancreatic
cancer based on SMAD4 profiles

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Liang Li
1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College,
China
Chemoresistance to gemcitabine limits its clinical implementation for pancreatic ductal adenocarcinoma
(PDAC). We previously generated an antibody drug conjugate (ADC)-like agent, EGFR/HER2 dual-targeting
ligand-based lidamycin (DTLL), and studied the effect of DTLL combined with gemcitabine and the potential
role of SMAD4 in the chemoresistance of PDAC. On the basis of SMAD4 profiles in in vitro and in vivo
models, we investigated the antitumor effects of DTLL, gemcitabine and their combination, followed with
mechanistic characterization. The results suggested that DTLL combination treatment with gemcitabine
significantly repressed tumors with remarkably enhanced efficacy as compared to gemcitabine or DTLL
alone given in either SMAD4-deficient/gemcitabine-resistant or SMAD4-sufficient/gemcitabinesensitive
cell line derived xenograft (CDX) and patient derived xenograft (PDX) tumors, respectively. Functional
studies indicated that SMAD4 genetic status is responsible for SMAD4 protein level which determines
different cellular susceptibility of PDAC. R100T mutation contributes to loss of SMAD4 protein and function
with rapid protein degradation, leading to resistance to gemcitabine in PDAC cells. Moreover, DTLL
significantly altered the protein half-life time and level of mutant and wild-type SMAD4 by inhibiting protein
degradation at different velocities and distinctly changing the interaction of SMAD4 with TRIM33.
Mechanism studies implied that DTLL combinational treatment might not only prevent from neoplastic
proliferation via blockage of ATK/mTOR signaling and antiapoptotic proteins (BCL-2 and MCL1)
mediated by impaired NF-kB function in SMAD4-sufficient/gemcitabine-sensitive PDAC cells, but also
restore the bioactivity of SMAD4 as a tumor suppressor to trigger its downstream NF-kB-regulated signaling
of cell apoptosis in SMAD4- deficient/gemcitabine-resistant tumors. In conclusion, SMAD4 is the key central
mediator of not only the occurrence and development but also susceptibility in PDAC. DTLL sensitized
gemcitabine efficacy via distinct action mechanisms based on SMAD4 profiles in SMAD4-
sufficient/gemcitabine-sensitive and SMAD4-deficient/- resistant PDAC, respectively. Our findings provide
insight into a rational SMAD4-directed precision treatment strategy and reveal a promising DTLL
combination therapy to overcome chemoresistance in gemcitabine-resistant PDAC.
Key words: SMAD4; Pancreatic ductal adenocarcinoma (PDAC), Gemcitabine, Chemoresistance, Dual-
targeting ligand-based lidamycin (DTLL), Antibody drug conjugate (ADC)

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