The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax

B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as...

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Published in:	Hemato Vol. 5; no. 3; pp. 321 - 340
Main Authors:	Eiken, Alexandria P, Schmitz, Elizabeth, Drengler, Erin M, Smith, Audrey L, Skupa, Sydney A, Mohan, Kabhilan, Rana, Sandeep, Singh, Sarbjit, Mallareddy, Jayapal Reddy, Mathew, Grinu, Natarajan, Amarnath, El-Gamal, Dalia
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-09-2024
Subjects:	Apoptosis Cell death chronic lymphocytic leukemia (CLL) Cysts Cytotoxicity Drug resistance Ferroptosis ibrutinib Kinases Leukemia Lipid peroxidation Lipids Lymphoma Membranes Mutation Oxidative stress Proteins SpiD3 unfolded protein response (UPR) venetoclax St Louis Missouri United States > US ibrutinib chronic lymphocytic leukemia (CLL) ferroptosis unfolded protein response (UPR) drug resistance venetoclax SpiD3 oxidative stress
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Summary:	B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells. We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells. The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics. Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author Contributions: A.P.E., E.S. and E.M.D. performed experiments and analyzed the data; A.L.S. and S.A.S. developed the resistant cell lines and assisted in data analysis. A.P.E., E.S., A.N. and D.E.-G. contributed to the conceptualization, experimental design, and interpretation of the results. S.R., S.S., J.R.M. and A.N. synthesized SpiD3. K.M. and G.M. assisted with the RNA-sequencing analysis. A.P.E., E.S. and D.E.-G. wrote the original manuscript. All other authors reviewed and edited the manuscript. D.E.-G. managed and supervised all study aspects. All authors have read and agreed to the published version of the manuscript.
ISSN:	2673-6357 2673-6357
DOI:	10.3390/hemato5030024