Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects.

Autor:	Eiken AP; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Smith AL; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Skupa SA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Schmitz E; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Rana S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Singh S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Kumar S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., Mallareddy JR; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska., de Cubas AA; Department of Microbiology and Immunology, College of Medicine, Medical University of South Carolina, Charleston, South Carolina., Krishna A; Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska., Kalluchi A; Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska., Rowley MJ; Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska., D'Angelo CR; Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska., Lunning MA; Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska., Bociek RG; Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska., Vose JM; Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska., Natarajan A; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.; Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska., El-Gamal D; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 May 22; Vol. 4 (5), pp. 1328-1343.
DOI:	10.1158/2767-9764.CRC-24-0071
Abstrakt:	Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli. Significance: SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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