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Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma

Elena Battistello, Natalya Katanayeva, Elie Dheilly, Daniele Tavernari, Maria C. Donaldson, Luca Bonsignore, Margot Thome-Miazza, Amanda L. Christie, Mark A. Murakami, Olivier Michielin, Giovanni Ciriello, Vincent Zoete and Elisa Oricchio

Key points

  • Inhibition of BTK in patients that are resistant to ibrutinib changes signaling tumor dependencies and promotes MYC up-regulation.

  • Multi-target inhibition of LYN, FYN and BLK is therapeutically effective in DLBCL patients independently of their molecular subtypes.

Abstract

In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of DLBCL patients. Here, we used lymphoma cells isolated from DLBCL patients to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC up-regulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in DLBCL patient-derived xenografts and cell lines independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients.

  • Submitted October 2, 2017.
  • Accepted March 13, 2018.