論文 - 詳細
| RRC ID | 83334 |
|---|---|
| 著者 | Eiken AP, Smith AL, Skupa SA, Schmitz E, Rana S, Singh S, Kumar S, Mallareddy JR, de Cubas AA, Krishna A, Kalluchi A, Rowley MJ, D'Angelo CR, Lunning MA, Bociek RG, Vose JM, Natarajan A, El-Gamal D. |
| タイトル | Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects. |
| ジャーナル | Cancer Res Commun |
| Abstract |
UNLABELLED: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. |
| 巻・号 | 4(5) |
| ページ | 1328-1343 |
| 公開日 | 2024-5-22 |
| DOI | 10.1158/2767-9764.CRC-24-0071 |
| PII | 745101 |
| PMID | 38687198 |
| PMC | PMC11110724 |
| MeSH | Adenine / analogs & derivatives Adenine / pharmacology Animals Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Drug Resistance, Neoplasm / drug effects Humans Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy Leukemia, Lymphocytic, Chronic, B-Cell* / metabolism Leukemia, Lymphocytic, Chronic, B-Cell* / pathology Mice NF-kappa B / metabolism Piperidines / pharmacology Piperidines / therapeutic use Receptors, Antigen, B-Cell / metabolism Signal Transduction* / drug effects Spiro Compounds / pharmacology Spiro Compounds / therapeutic use Tumor Microenvironment / drug effects Unfolded Protein Response / drug effects |
| リソース情報 | |
| ヒト・動物細胞 | 9-15C(RCB2323) |