Galas-Filipowicz, Daria Ewa;
(2025)
Characterising the protective effect of stroma on Carfilzomib mediated cytotoxicity in Multiple Myeloma.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Multiple myeloma (MM) is a common hematologic malignancy characterised by malignant plasma cell accumulation in the bone marrow. Despite recent progress, MM remains incurable. MM cells heavily rely on unfolded protein response (UPR) signalling and proteasome degradation, making them vulnerable to proteasome inhibitors (PIs) like carfilzomib. However, acquired drug resistance, partly due to interactions with the bone marrow stromal environment, remains a major obstacle in MM treatment. The objective of this study was to investigate the impact of the stromal microenvironment on resistance to carfilzomib treatment in multiple myeloma. Co-cultures using the HS5 stromal cell line were employed to simulate stromal interactions with multiple myeloma cells. A significant reduction in the effectiveness of carfilzomib-induced cytotoxicity was observed when multiple myeloma cells were co-cultured with stromal cells, particularly when there was direct contact between the cells. Mitochondrial-mediated apoptosis was identified as the primary mechanism of carfilzomib-induced cell death, leading us to hypothesise that upregulated anti-apoptotic proteins, specifically MCL-1 and BCL-XL, might influence the response to proteasome inhibition. Both stromal interactions and carfilzomib treatment were found to upregulate the expression of MCL-1 and increase the dependence on BCL-XL. Therefore, we investigated the combined effect of these anti-apoptotic proteins on carfilzomib resistance. When both BCL-XL and MCL-1 were inhibited using lower concentrations of BH3 mimetics, multiple myeloma cells became highly susceptible to carfilzomib-mediated cytotoxicity in the presence of stroma. 4 Immunoprecipitation experiments with BIM further confirmed this switch in survival dependency between pro-survival proteins when MCL-1 or BCL-XL inhibitors were used. It was concluded that the upregulation of pro-survival proteins by stroma contributes to the resistance of multiple myeloma cells to proteasome inhibitors, and simultaneous blockade of BCL-XL and MCL-1 is necessary to overcome the protective effect of the stroma and restore sensitivity to carfilzomib. The combination of subtherapeutic doses of BH-3 mimetic drugs with proteasome inhibitors holds promise as a potential therapeutic strategy for multiple myeloma.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Characterising the protective effect of stroma on Carfilzomib mediated cytotoxicity in Multiple Myeloma |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203063 |
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