Killing of Resistant Cancer Cells with Low Bak by a Combination of an Anti-mesothelin Immunotoxin and a TRAIL Receptor 2 Agonist Antibody.
Clin Cancer Res. 2011 Aug 3;
Authors: Du X, Xiang L, Mackall CL, Pastan I
PURPOSE: Many solid tumors express cell surface mesothelin making them attractive targets for antibody-based therapies of cancer. SS1P (anti-mesothelin(Fv)PE38) is a recombinant immunotoxin (RIT) that has potent cytotoxic activity on several cancer cell lines and clinical activity in mesothelioma patients. Pancreatic cancers express mesothelin and are known to be resistant to most chemotherapeutic agents. The goal of the current study is to treat pancreatic cancer with RIT by targeting mesothelin. EXPERIMENTAL DESIGN: We measured the cytotoxic activity of an anti-mesothelin immunotoxin on pancreatic cancer cells. We also measured the levels of several pro- and anti-apoptotic proteins, as well as the ability of TRAIL or the anti-TRAIL receptor 2 agonist antibody (HGS-ETR2) to kill pancreatic cells and the cytotoxic activity of the two agents together in cell culture and against tumors in mice.RESULTS: In two pancreatic cancer cell lines immunotoxin treatment inhibited protein synthesis, but did not produce significant cell death. The resistant lines had low levels of the pro-apoptotic protein Bak. Increasing Bak expression enhanced the sensitivity to immunotoxins, while Bak knockdown diminished it. We also found that combining immunotoxin with TRAIL or HGS-ETR2 caused synergistic cell death, and together triggered caspase-8 recruitment and activation, Bid cleavage and Bax activation. Combining SS1P with HGS-ETR2 also acted synergistically to decrease tumor burden in a mouse model. CONCLUSIONS: Our data show that low Bak can cause cancer cells to be resistant to immunotoxin treatment, and that combining immunotoxin with TRAIL or a TRAIL agonist antibody can overcome resistance.
PMID: 21813632 [PubMed - as supplied by publisher]
You can link to this article on your web site using following code:
We're looking for comments that are interesting, substantial or highly amusing. If your comments are excessively self-promotional (use your real name, no keywords please), obnoxious, or even worse, boring, you will be banned from commenting. Your comment must be related to the post. Please do not comment on how great or wonderful the post is. All comments are moderated and, if approved, will display in less than 24 hours.