ArticleJournal of immunotherapy (Hagerstown, Md. : 1997)2014
Combining the antimesothelin immunotoxin SS1P with the BH3-mimetic ABT-737 induces cell death in SS1P-resistant pancreatic cancer cells.
Article in Journal of immunotherapy (Hagerstown, Md. : 1997), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
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- Mechanisms of Resistance to Immunotoxins ContainingBiomolecules · 2020Review
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- Synergistic antitumor effects of 9.2.27-PE38KDEL and ABT-737 in primary and metastatic brain tumors.PloS one · 2019Article
- Tumor-Specific Induction of the Intrinsic Apoptotic Pathway-A New Therapeutic Option for Advanced Prostate Cancer?Frontiers in oncology · 2019Article
- The Role of Mesothelin as a Diagnostic and Therapeutic Target in Pancreatic Ductal Adenocarcinoma: A Comprehensive Review.Targeted oncology · 2018Review
- Synergistic cytotoxicity of a prostate cancer-specific immunotoxin in combination with the BH3 mimetic ABT-737.Cancer immunology, immunotherapy : CII · 2018Article
- Essential role for Bim in mediating the apoptotic and antitumor activities of immunotoxins.Oncogene · 2017Article
- BH3 Mimetics for the Treatment of Prostate Cancer.Frontiers in pharmacology · 2017Article
- Chemical Screens Identify Drugs that Enhance or Mitigate Cellular Responses to Antibody-Toxin Fusion Proteins.PloS one · 2016Article
- New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma.Scientific reports · 2015Article
- Article
- In vitro and in vivo activity of the low-immunogenic antimesothelin immunotoxin RG7787 in pancreatic cancer.Molecular cancer therapeutics · 2014Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
SS1P is an antimesothelin recombinant immunotoxin (RIT). Pancreatic ductal adenocarcinoma (PDAC) cell lines are resistant to SS1P, despite high mesothelin expression. The aim of this study is to examine whether combining SS1P and BH3-mimetic ABT-737 induces cell death in a panel of PDAC cell lines. ABT-737 binds and neutralizes several antiapoptotic BCL2 family proteins, but has a low affinity for the short-lived MCL1 and BCL2A1. SS1P inhibits protein synthesis, which has shown to downregulate MCL1. PDAC cell lines KLM-1, BxPc-3, and Panc 3.014 were resistant to SS1P or ABT-737 alone. Combining both compounds led to a significant increase in cell death. After 48 hours of treatment, cell death was observed in 92% of KLM-1, 55% of BxPc-3, and 23% of Panc 3.014 cells. Panc 3.014 had the highest number of mesothelin-binding sites (92×10(3)), followed by KLM-1 (58×10(3)) and BxPc-3 (3×10(3)). ABT-737 had no effect on SS1P internalization, but enhanced SS1P-induced protein synthesis inhibition significantly in KLM-1, to a lesser extent in BxPc-3, and very little in Panc 3.014. SS1P alone or in combination with ABT-737 downregulated MCL1 in KLM-1 and BxPc-3, but not in Panc 3.014. Similar observations were made for BCL2A1, which had the highest levels in Panc 3.014. Compared with KLM-1, Panc 3.014, and BxPc-3 also had lower proapoptotic BAK and a trend toward higher MCL1. Proapoptotic BAX was similar in KLM-1 and BxPc-3, but lower in Panc 3.014. In conclusion, combining SS1P with ABT-737 overcomes SS1P-resistance in PDAC, although to a variable extent. The efficacy of the combination is mainly associated with the RIT-associated inhibition of protein synthesis and the ability to downregulate MCL1 and BCL2A1, while levels of other key apoptotic proteins may also be important. Our data support the combination of an RIT and a BH3-mimetic, and identify factors that potentially limit the efficacy of such therapeutic approach.
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