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Identification of kinase inhibitors that overcome venetoclax resistance in activated CLL cells by high-content screening

Sina Oppermann, Jarkko Ylanko, Yonghong Shi, Santosh Hariharan, Christopher C. Oakes, Patrick M. Brauer, Juan C. Zúñiga-Pflücker, Brian Leber, David E. Spaner and David W. Andrews

Key points

  • Patient-specific pathways of resistance to venetoclax can be identified by high-content screening of clinical samples with a kinase inhibitor library.

  • Sunitinib may effectively overcome resistance to venetoclax for many patients by down-regulating the expression of Bcl-xl, Mcl-1, and A1 in CLL cells.

Abstract

Novel agents such as the Bcl-2-inhibitor venetoclax (ABT-199) are changing treatment paradigms for Chronic Lymphocytic Leukemia (CLL) but important problems remain. While some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor sub-populations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KI) to identify agents that may improve venetoclax therapy in a personalized manner. Marked inter-patient variability was noted for which KIs were effective; nevertheless sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that up-regulate anti-apoptotic Bcl-xl, Mcl-1 and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. While patient-specific drug responses are common, for many patients combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax.

  • Submitted December 21, 2015.
  • Accepted June 8, 2016.