Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies

• DOI: 10.4161/mabs.32106
• Publication Date: 2014-08-04T18:01:57Z
• Authors: Magdalena Winiarska; Kamil Bojarczuk; Beata Pyrzynska; Jacek Bil; Marta Siernicka; Michal Dwojak; Malgorzata Bobrowicz; Nina Miazek; Piotr Zapala; Agnieszka Zagozdzon; Magdalena Krol; Aleksandra Syta; Paulina Podszywal...; Zofia Pilch; Anna Dabrowska-Iw...; Przemyslaw Juszcz...; Dimitar G Efremov; Mikolaj Slabicki; Thorsten Zenz; Aude Le Roy; Daniel Olive; Tomasz P Rygiel; Jeanette HW Leusen; Jakub Golab
• Keywords: 0301 basic medicine; Blotting, Western; Antibody-Dependent Cell Cytotoxicity; Dasatinib; Antibodies, Monoclonal; Antigens, CD20; 3. Good health; Gene Expression Regulation, Neoplastic; Killer Cells, Natural; Mice, Inbred C57BL; Antibodies, Monoclonal, Murine-Derived; Disease Models, Animal; 03 medical and health sciences; HEK293 Cells; Cell Line, Tumor; Neoplasms; Animals; Humans; Female; K562 Cells; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Reports; Oligonucleotide Array Sequence Analysis

Clinical trials with SRC family kinases (SFKs) inhibitors used alone or in a combination with anti-CD20 monoclonal antibodies (mAbs) are currently underway in the treatment of B-cell tumors. However, molecular interactions between these therapeutics have not been studied so far. A transcriptional profiling of tumor cells incubated with SFKs inhibitors revealed strong downregulation of MS4A1 gene encoding CD20 antigen. In a panel of primary and established B-cell tumors we observed that SFKs inhibitors strongly affect CD20 expression at the transcriptional level, leading to inhibition of anti-CD20 mAbs binding and increased resistance of tumor cells to complement-dependent cytotoxicity. Activation of the AKT signaling pathway significantly protected cells from dasatinib-triggered CD20 downregulation. Additionally, SFKs inhibitors suppressed antibody-dependent cell-mediated cytotoxicity by direct inhibition of natural killer cells. Abrogation of antitumor activity of rituximab was also observed in vivo in a mouse model. Noteworthy, the effects of SFKs inhibitors on NK cell function are largely reversible. The results of our studies indicate that development of optimal combinations of novel treatment modalities with anti-CD20 mAbs should be preceded by detailed preclinical evaluation of their effects on target cells.