Review
Hematology
Andrew W. Roberts, Andrew H. Wei, David C. S. Huang
Summary: BH3 mimetics are a new class of anticancer drugs that target prosurvival BCL2 proteins to induce apoptosis, with Venetoclax being the first approved BCL2 inhibitor showing activity in various lymphoid and myeloid neoplasms. Long-term exposure may lead to secondary resistance. Success of BCL2 inhibitors has led to development of BH3 mimetics targeting MCL1, with promising preclinical activity but potential challenges due to MCL1's physiological roles in nonhematologic tissues.
Article
Hematology
Neeta Bala Tannan, Mandana T. Manzari, Laurie Herviou, Mariana Da Silva Ferreira, Connor Hagen, Hiroto Kiguchi, Katia Manova-Todorova, Venkatraman Seshan, Elisa de Stanchina, Daniel A. Heller, Anas Younes
Summary: Dual targeting of MCL1 and BCL2 proteins using S63845 and venetoclax induces durable remissions in DLBCL tumors in mice, but is accompanied by hematologic toxicity and weight loss. Encapsulation into nanoparticles targeting P-selectin reduces toxicity, enhances tumor drug enrichment, and allows for a reduction in drug dose.
Article
Hematology
Irene Peris, Silvia Romero-Murillo, Elena Martinez-Balsalobre, Caroline C. Farrington, Elena Arriazu, Nerea Marcotegui, Marta Jimenez-Munoz, Cristina Alburquerque-Prieto, Andrea Torres-Lopez, Vicente Fresquet, Jose A. Martinez-Climent, Maria C. Mateos, Maria L. Cayuela, Goutham Narla, Maria D. Odero, Carmen Vicente
Summary: Venetoclax combination therapies are becoming the standard of care in AML, but their efficacy in older/unfit patients is limited, highlighting the need for more effective therapies. Reactivating protein phosphatase 2A (PP2A) enhances venetoclax activity in AML cells by modulating BCL2 dependency and extracellular signal-regulated kinase signaling. Targeting PP2A increases the efficacy of venetoclax and azacitidine combination therapy in AML.
Article
Biochemistry & Molecular Biology
Yu-Jun Dai, Si-Yuan He, Fang Hu, Xue-Ping Li, Jian-Ming Zhang, Si-Liang Chen, Wei-Na Zhang, Hai-Min Sun, Da-Wei Wang
Summary: The proportion of NK cells in the bone marrow could predict the prognosis of ND-AML patients, and combination of MCL1 inhibitor with NK cell-based immunotherapy could effectively improve therapeutic efficiency.
Article
Biochemistry & Molecular Biology
Shuning He, Mark W. Zimmerman, Hillary M. Layden, Alla Berezovskaya, Julia Etchin, Megan W. Martel, Grace Thurston, Chang-Bin Jing, Ellen van Rooijen, Charles K. Kaufman, Scott J. Rodig, Leonard I. Zon, E. Elizabeth Patton, Marc R. Mansour, A. Thomas Look
Summary: Loss of the NF1 tumor suppressor gene can lead to aggressive melanomas with a high risk of treatment failure. This study established a zebrafish model of NF1-mutant melanomas harboring PTEN loss and demonstrated that mTOR inhibitors and a three-drug combination can potently induce apoptosis in NF1/PTEN-deficient melanoma cells, supporting the need for early-stage clinical trials in patients.
Article
Biochemistry & Molecular Biology
Jing-Ting Chiou, Yuan-Chin Lee, Liang-Jun Wang, Long-Sen Chang
Summary: This study found that human leukemia U937 cells continuously treated with hydroquinone (HQ) showed reduced sensitivity to BCL2 and BCL2L1 inhibitors. However, the combination of WEHI-539 and ABT-199 or ABT-263 showed synergistic cytotoxicity to U937 and U937/HQ cells. Further investigation revealed that the combined treatment induced autophagy, accelerated beta-TrCP mRNA degradation, and led to NOXA-dependent MCL1 degradation.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Article
Chemistry, Multidisciplinary
Jiguo Xie, Xiaofei Zhao, Peng Zhang, Yueyue Zhang, Ru Cheng, Zhiyuan Zhong, Chao Deng
Summary: This study adopts phenylboronic acid-functionalized polypeptide nanovehicles for co-delivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors to achieve synergistic and potent treatment of AML. The nanovehicles exhibit efficient and robust drug coencapsulation using dynamic boronic ester bonds, B-N coordination, and pi-pi stacking. In both mouse and cell models, the nanoparticles show significant anti-tumor activity and hold great potential for AML treatment.
Article
Oncology
Ophelie Champion, Alana Soler, Sophie Maiga, Celine Bellanger, Catherine Pellat-Deceunynck, Alexis Talbot, Cyrille Touzeau, Martine Amiot, Patricia Gomez-Bougie
Summary: Secondary plasma cell leukemia (sPCL) is a rare and aggressive plasma cell malignancy with limited therapeutic options. Our study showed that BH3 mimetics targeting BCL2 or BCLXL effectively killed certain sPCL. Furthermore, the use of DT2216, a BCLXL proteolysis targeting chimera compound, could degrade BCLXL without causing thrombocytopenia and induce apoptotic cell death in myeloma cells, suggesting its potential therapeutic benefit for sPCL patients addicted to BCLXL.
FRONTIERS IN ONCOLOGY
(2023)
Article
Oncology
Magdalena Klanova, Dmitry Kazantsev, Eva Pokorna, Tomas Zikmund, Jana Karolova, Matej Behounek, Nicol Renesova, Dana Sovilj, Cristina D. Kelemen, Karel Helman, Radek Jaksa, Ondrej Havranek, Ladislav Andera, Marek Trneny, Pavel Klener
Summary: MCL1 is a critical survival molecule for most Burkitt lymphomas and a subset of BCL2-negative DLBCLs. The levels of BCL2 and MCL1 expression and the occupational status of MCL1 are key factors in modulating sensitivity/resistance to S63845.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Nizar M. Mhaidat, Haneen Amawi, Karem H. Alzoubi
Summary: The study investigated three SNPs in the promoter region of antiapoptotic genes in Jordanian patients with colorectal cancer and found that BCL2 rs2279115 and MCL1 rs9803935 SNPs were significantly distributed and associated with disease progression and metastasis, while BCL2 rs4987852 SNP showed no association with disease variables.
CURRENT PHARMACEUTICAL BIOTECHNOLOGY
(2021)
Article
Cell Biology
Katarzyna Lipska, Agata Filip, Anna Gumieniczek
Summary: The combination of chlorambucil and valproic acid may lead to increased apoptosis in CLL cells and elevated expression of important genes, suggesting further investigation into this treatment approach for CLL.
Article
Multidisciplinary Sciences
Gerard Duart, Assaf Elazar, Jonathan Y. Weinstein, Laura Gadea-Salom, Juan Ortiz-Mateu, Sarel J. Fleishman, Ismael Mingarro, Luis Martinez-Gil
Summary: Several methods have been developed to explore protein-protein interactions, but there is a need for more research on targeting transmembrane domains (TMDs). This study developed a computational approach to design sequences that can modulate protein-protein interactions in the membrane, and successfully applied it to BclxL. The findings enhance our understanding of protein-protein interactions in membranes and may lead to the development of inhibitors targeting TMD interactions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Hematology
Jordy C. G. van der Zwet, Valentina Cordo, Jessica G. C. A. M. Buijs-Gladdines, Rico Hagelaar, Willem K. Smits, Eric Vroegindeweij, Laura T. M. Graus, Vera M. Poort, Marloes Nulle, Rob Pieters, Jules P. P. Meijerink
Summary: A study found that physiological and pathogenic IL7R-induced signaling can cause glucocorticoid resistance in a subset of pediatric T-ALL patients. The activation of STAT5 alone is insufficient to raise cellular steroid resistance, and the upregulation of anti-apoptotic genes BCL2 and BCL-XL requires steroid-induced activation of NR3C1. Isolated STAT5 activation does not directly impair the steroid response.
Article
Virology
Daniel Dunham, Prasanth Viswanathan, Jackson Gill, Mark Manzano
Summary: Kaposi's sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL) and PEL cell lines show addiction to MCL1 for survival. MCL1 functions mainly to prevent BAX/BAK1-mediated apoptosis in PEL cells, and its selective requirement is due to its excess expression over the BCL2 family.
JOURNAL OF VIROLOGY
(2022)
Article
Cell Biology
Dechen Fu, Luke Pfannenstiel, Abeba Demelash, Yee Peng Phoon, Cameron Mayell, Claudia Cabrera, Caini Liu, Junjie Zhao, Josephine Dermawan, Deepa Patil, Jennifer DeVecchio, Matthew Kalady, Andrew J. Souers, Darren C. Phillips, Xiaoxia Li, Brian Gastman
Summary: Chemotherapy-induced MCL1 translocation represents a novel resistance mechanism in colorectal cancer (CRC), especially in p53(null) CRC. Additionally, MCL1 nuclear translocation confers sensitivity to Bcl-xL inhibitors in chemotherapy-treated p53(-/-) CRC models, indicating potential therapeutic strategies for this type of cancer.
CELL DEATH & DISEASE
(2022)