Targeting metabolic reprogramming in metastatic colorectal and prostate cancer cells to prevent therapeutic failure
[eng] Prostate and colorectal cancer are among the cancer types with the highest recurrence and mortality rates. The emergence of drug resistance poses a considerable challenge for effective treatment, especially in the advanced stages of the disease. Metabolic reprogramming is a crucial contributor...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/212420 |
| Acceso en línea: | https://hdl.handle.net/2445/212420 http://hdl.handle.net/10803/691271 |
| Access Level: | acceso abierto |
| Palabra clave: | Oncologia Metabolisme Terapèutica Resistència als medicaments Oncology Metabolism Therapeutics Drug resistance |
| Sumario: | [eng] Prostate and colorectal cancer are among the cancer types with the highest recurrence and mortality rates. The emergence of drug resistance poses a considerable challenge for effective treatment, especially in the advanced stages of the disease. Metabolic reprogramming is a crucial contributor to the adaptative process of drug resistance and a key hallmark of cancer that enables tumor cells to meet the metabolic and energetic requirements for tumor survival and progression. Then, targeting metabolic reprogramming represents a promising anti-cancer strategy, and understanding the metabolic alterations acquired after drug resistance can provide valuable insights for developing effective combination therapies. In this work, we study metabolic alterations underlying Oxaliplatin, an alkylating agent that impairs DNA replication and transcription by promoting DNA damage through the generation of platinum crosslinks, and Palbociclib, a selective inhibitor of cyclin- dependent kinases 4 and 6 (CDK4/6) that arrests cells in the G1/G0 phase of the cell cycle. Both compounds are commonly employed in cancer therapies and have exhibited efficacy in several types of cancer. This work assesses the metabolic characterization of drug resistance acquisition after these treatments in advanced stages of colorectal and prostate cancer cells, focusing on the aggressive SW620 and PC-3 cell lines, respectively. Based on the metabolic characterization, transcriptomic, and respiratory data, or applying cell-line-specific metabolic reconstructions after data integration using Genome-Scale Metabolic Models (GSMM), our results identify metabolic vulnerabilities in drug-adapted phenotypes and reveal key metabolic pathways on which cancer cells rely to adapt and survive, serving as attractive targets for therapeutic interventions. These pathways include but are not limited to glycolysis, fatty acid metabolism, amino acid metabolism, and oxidative phosphorylation. Our strategy proposes rational therapeutic combinations with Oxaliplatin or Palbociclib to overcome drug resistance in advanced-stage prostate and colorectal cancers based on drug repurposing. These findings include the interaction between metabolic reprogramming and cell cycle regulation, promoting cell cycle arrest in the G1/G0 phase to address Oxaliplatin resistance, and targeting oxidative phosphorylation, mitochondrial metabolism, and reactive oxygen species (ROS) modulation to sensitize cells to Palbociclib. Notably, Palbociclib combination with a ROS modulator represents a successful approach that expands the potential of application across different colorectal models, showing efficacy in preclinical models, significantly compromising in vivo tumor progression in NOD/SCID mice with SW620 tumors and in vitro cell proliferation in both the metastatic SW620 and the primary colorectal cancer HCT116 cell lines. Based on the metabolic reprogramming underlying Oxaliplatin and Palbociclib treatments, this work provides alternative combination therapies by targeting metabolic vulnerabilities that could be further explored to improve treatment outcomes and overcome drug resistance in advanced stages of prostate and colorectal cancers. |
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