Dataset Information

Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma.

ABSTRACT:

Background

Neuroblastoma is a paediatric cancer that is characterised by poor prognosis for chemoresistant disease, highlighting the need for better treatment options. Here, we asked whether BH3-mimetics inhibiting BCL2 proteins may eliminate chemoresistant neuroblastoma cells.

Methods

We utilised cisplatin-adapted neuroblastoma cell lines as well as patient tissues before and after relapse to study alterations of BCL2 proteins upon chemoresistance.

Results

In a direct comparison of cisplatin-resistant cells we identified a prominent loss of sensitivity to BCL2/BCL-X_L inhibitors that is associated with an increase in MCL1 dependency and high expression of MCL1 in patient tumour tissues. Screening of FDA-approved anti-cancer drugs in chemoresistant cells identified therapeutics that may be beneficial in combination with the clinically tested BH3-mimetic ABT263, but no synergistic drug interactions with the selective MCL1 inhibitor S63845. Further exploration of potential treatment options for chemoresistant neuroblastoma identified immunotherapy based on NK cells as highly promising, since NK cells are able to efficiently kill both parental and chemoresistant cells.

Conclusions

These data highlight that the application of BH3-mimetics may differ between first line treatment and relapsed disease. Combination of NK cell-based immunotherapy with BH3-mimetics may further increase killing of chemoresistant neuroblastoma, outlining a new treatment strategy for relapsed neuroblastoma.

SUBMITTER: Jacob M

PROVIDER: S-EPMC10646009 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma.

Jacob Maureen M Wiedemann Sara S Brücher Daniela D Pieper Nadja M NM Birkhold Moni M Särchen Vinzenz V Jeroch Jan J Demes Melanie C MC Gretser Steffen S Braun Yannick Y Gradhand Elise E Rothweiler Florian F Michaelis Martin M Cinatl Jindrich J Vogler Meike M

British journal of cancer 20230919 10

<h4>Background</h4>Neuroblastoma is a paediatric cancer that is characterised by poor prognosis for chemoresistant disease, highlighting the need for better treatment options. Here, we asked whether BH3-mimetics inhibiting BCL2 proteins may eliminate chemoresistant neuroblastoma cells.<h4>Methods</h4>We utilised cisplatin-adapted neuroblastoma cell lines as well as patient tissues before and after relapse to study alterations of BCL2 proteins upon chemoresistance.<h4>Results</h4>In a direct comp ...[more]

PMID: 37723317

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Project description:Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action-direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs.

Dataset Information

Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma.

Background

Methods

Results

Conclusions

Publications

Increased MCL1 dependency leads to new applications of BH3-mimetics in drug-resistant neuroblastoma.

Similar Datasets

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