title: Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies.
abstract: 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.
authors.affiliation: a Department of Immunology; Center for Biostructure Research ; Medical University of Warsaw ; Warsaw , Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Winiarska
authors.forename: Kamil
authors.initials: K
authors.lastname: Bojarczuk
authors.forename: Beata
authors.initials: B
authors.lastname: Pyrzynska
authors.forename: Jacek
authors.initials: J
authors.lastname: Bil
authors.forename: Marta
authors.initials: M
authors.lastname: Siernicka
authors.forename: Michal
authors.initials: M
authors.lastname: Dwojak
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Bobrowicz
authors.forename: Nina
authors.initials: N
authors.lastname: Miazek
authors.forename: Piotr
authors.initials: P
authors.lastname: Zapala
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zagozdzon
authors.forename: Magdalena
authors.initials: M
authors.lastname: Krol
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Syta
authors.forename: Paulina
authors.initials: P
authors.lastname: Podszywalow-Bartnicka
authors.forename: Zofia
authors.initials: Z
authors.lastname: Pilch
authors.forename: Anna
authors.initials: A
authors.lastname: Dabrowska-Iwanicka
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
authors.forename: Dimitar G
authors.initials: DG
authors.lastname: Efremov
authors.forename: Mikolaj
authors.initials: M
authors.lastname: Slabicki
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.forename: Aude
authors.initials: A
authors.lastname: Le Roy
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.forename: Tomasz P
authors.initials: TP
authors.lastname: Rygiel
authors.forename: Jeanette H W
authors.initials: JH
authors.lastname: Leusen
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000276:immunology* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011743:Pyrimidines / Q000276:immunology / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013844:Thiazoles / Q000276:immunology / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069283:Rituximab; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D000069439:Dasatinib
keywords: ADCC, antibody-dependent cell-mediated cytotoxicity; BCR, B-cell receptor; CD20; CDC, complement-dependent cytotoxicity; CFSE, carboxyfluorescein succinimidyl ester; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; NHL, non-Hodgkin lymphoma; PBMC, peripheral blood mononuclear cells; SFKs, SRC family kinases; SRC family kinases; dasatinib; ofatumumab; rituximab