Acquired Resistance to PRMT5 Inhibition in Mantle Cell Lymphoma Is Associated with Compensatory Activation of Multiple Signaling Pathways

Long, Mackenzie; Koirala, Shirsha; Sloan, Shelby; Brown, Fiona; Tallada, Sheetal; Hinterschied, Claire; Corps, Kara N.; Helmig-Mason, JoBeth; Chung, Ji Hyun; Scherle, Peggy; Vaddi, Kris; Meydan, Cem; Foox, Jonathan; Butler, Daniel; Mason, Christopher E.; Alinari, Lapo; Blaser, Bradley W.; Baiocchi, Robert A.

doi:10.1182/blood-2022-164641

Cited by 1 publication

(1 citation statement)

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“…Though PRMT5 inhibition emerged as an attractive therapeutic target in MCL, a recent study has also identified the development of primary or acquired resistance to PRMT5 inhibitors in MCL. PRMT5 inhibitor-resistant MCLs exhibited compensatory activation of multiple signaling pathways such as insulin receptors, PI3K, MAPK, and mTOR signaling in tumors, further using PRMT5 inhibitor (PRT-382) in combination with PI3K/mTORC1 and 2 (Omipalisib), or mTORC1 (Temsirolimus) or EIF1A (Silvestrol) could reverse this PRMT5 resistance in MCL [ 132 ].…”

Section: Chromatin Modifiersmentioning

confidence: 99%

Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

Jain,

Mamgain,

Chowdhury

et al. 2023

J Hematol Oncol

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Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2–6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton's tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody–drug conjugates.

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Section: Chromatin Modifiersmentioning

confidence: 99%