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.

Identification of BLNK and BTK as mediators of rituximab‐induced programmed cell death by CRISPR screens in GCB‐subtype diffuse large B‐cell lymphoma

“…Expression of CD20 was only vaguely reduced in OCI-Ly-7 cells upon BLNK and BTK KO, whereas lack of BLNK or BTK led to a marked reduction of CD20 levels in SU-DHL-5 cells. Our observations are in line with previous studies showing that interference with BCR signaling, by treatment with SRC family kinase inhibitors and BTK inhibitors, leads to reduced MS4A1 expression [66][67][68][69].…”

AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma

“…11 It is also possible that the adverse prognostic impact of AKT for patients treated with R-CHOP has been mitigated because rituximab could inhibit AKT signaling, 38 whereas AKT signaling up-regulates CD20 levels. 39 The overlapping but also independent regulation and function of p-AKT (Ser 473 ) and p-AKT (Thr 308 ) may also have confounded the analysis. Although phosphorylation at Ser 473 is generally thought necessary for the full activation of p-AKT, 9,10,40 p-AKT (Thr 308 ) in the absence of phospho-Ser 473 can have partial function.…”

Efficacy and safety of two pegfilgrastim biosimilars: Tripegfilgrastim and pegteograstim

“…Lymphoma, derived from lymphoid cell lines, may exhibit a stronger expression of G‐CSFR, 26‐28 resulting in dysregulated signaling pathways, including JAK/STAT, Src kinases, and PI3K, compared to solid cancers 29 . In addition, the anti‐CD20 agents and high‐dose steroids used in the treatment of B‐cell lineage lymphoma have been associated with STAT, 30‐32 Src kinases, 33,34 and PI3K 35,36 . These molecular changes may have affected receptor‐binding ability and our ability to distinguish between the efficacy of the reference pegfilgrastim and the biosimilars.…”