Antitumor effects of immunotoxins are enhanced by lowering HCK or treatment with SRC kinase inhibitors.

Abstract

Recombinant immunotoxins (RIT) are agents being developed for cancer treatment. They are composed of an Fv that binds to a cancer cell, fused to a 38-kDa fragment of Pseudomonas exotoxin A. SS1P is a RIT that targets mesothelin, a protein expressed on mesothelioma as well as pancreatic, ovarian, lung, and other cancers. Because the protein tyrosine kinase family regulates a variety of cellular processes and pathways, we hypothesized that tyrosine kinases might regulate susceptibility to immunotoxin killing. To investigate their role, we used siRNAs to lower the level of expression of the 88 known tyrosine kinases. We identified five tyrosine kinases, INSR, HCK, SRC, PDGFRβ, and BMX that enhance the activity of SS1P when their level of expression is lowered by siRNAs. We further investigated the Src family member HCK in this study. Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P. We investigated the mechanism of enhancement and found that HCK knockdown enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax. We then found that Src inhibitors mimic the stimulatory effect of HCK knockdown; both SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22-expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models. Our data suggest that the combination of immunotoxin with tyrosine kinase inhibitors may be an effective way to treat some cancers.

• Authors: Xiu-Fen Liu, Laiman Xiang, David J FitzGerald, Ira Pastan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 1 Pg. 82-9 (Jan 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24145282 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Aniline Compounds
• Antibodies, Monoclonal
• Bacterial Toxins
• Exotoxins
• Immunotoxins
• Indoles
• Msln protein, mouse
• Nitriles
• Quinolines
• SU 6656
• Sulfonamides
• immunotoxin HA22
• bosutinib
• src-Family Kinases
• Mesothelin

Topics

• Aniline Compounds (administration & dosage)
• Animals
• Antibodies, Monoclonal
• Bacterial Toxins (administration & dosage)
• Cell Line, Tumor
• Drug Synergism
• Exotoxins (administration & dosage)
• Gene Expression Regulation, Neoplastic (drug effects)
• Immunotoxins (administration & dosage)
• Indoles (administration & dosage)
• Mesothelin
• Mice
• Neoplasms (drug therapy, genetics, pathology)
• Nitriles (administration & dosage)
• Quinolines (administration & dosage)
• Sulfonamides (administration & dosage)
• Xenograft Model Antitumor Assays
• src-Family Kinases (antagonists & inhibitors, biosynthesis, genetics)