American Association for Cancer Research

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Supplementary Table 2 from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

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posted on 2023-04-04, 01:06 authored by Arthur L. Shaffer, James D. Phelan, James Q. Wang, DaWei Huang, George W. Wright, Monica Kasbekar, Jaewoo Choi, Ryan M. Young, Daniel E. Webster, Yandan Yang, Hong Zhao, Xin Yu, Weihong Xu, Sandrine Roulland, Michele Ceribelli, Xiaohu Zhang, Kelli M. Wilson, Lu Chen, Crystal McKnight, Carleen Klumpp-Thomas, Craig J. Thomas, Björn Häupl, Thomas Oellerich, Zachary Rae, Michael C. Kelly, Inhye E. Ahn, Clare Sun, Erika M. Gaglione, Wyndham H. Wilson, Adrian Wiestner, Louis M. Staudt

Supplemental Table2. Tracking the evolution of ibrutinib resistance phenotypes, relates to Fig. 2









The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)–dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies. In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought.See related commentary by Pasqualucci, p. 555.This article is highlighted in the In This Issue feature, p. 549