Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer
Abstract Colorectal cancer (CRC) treatment remains challenging due to genetic heterogeneity and resistance mechanisms. To address this, we developed a drug discovery pipeline using patient-derived primary CRC cultures with diverse genomic profiles. These cultures closely resemble certain molecular c...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-08649-0 |
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| author | Marcin Duleba Eliza Zimoląg Joanna Szuszkiewicz Marcin Serocki Joanna Szklarczyk Olga Dracz Alexander Kurzejamski Izabella Więckowska Marcelina Chmiel Barbara Lipert Katarzyna Sarad Joanna Krawczyk Oleksii Bryzghalov Agata Stachowicz-Wałaszek Karolina Pyziak Joanna Drozdowska Krzysztof Baczyński Konrad Wojtowicz Maurycy Chronowski Krzysztof Rataj Magdalena Otrocka Michał Mikula Paula Feliksiak Rafał Dziadziuszko Tomasz Rzymski Andrew Thomason Krzysztof Brzózka Andrzej Mazan |
| author_facet | Marcin Duleba Eliza Zimoląg Joanna Szuszkiewicz Marcin Serocki Joanna Szklarczyk Olga Dracz Alexander Kurzejamski Izabella Więckowska Marcelina Chmiel Barbara Lipert Katarzyna Sarad Joanna Krawczyk Oleksii Bryzghalov Agata Stachowicz-Wałaszek Karolina Pyziak Joanna Drozdowska Krzysztof Baczyński Konrad Wojtowicz Maurycy Chronowski Krzysztof Rataj Magdalena Otrocka Michał Mikula Paula Feliksiak Rafał Dziadziuszko Tomasz Rzymski Andrew Thomason Krzysztof Brzózka Andrzej Mazan |
| author_sort | Marcin Duleba |
| collection | DOAJ |
| description | Abstract Colorectal cancer (CRC) treatment remains challenging due to genetic heterogeneity and resistance mechanisms. To address this, we developed a drug discovery pipeline using patient-derived primary CRC cultures with diverse genomic profiles. These cultures closely resemble certain molecular characteristics of primary and metastatic CRC, highlighting their promise as a translational platform for therapeutic evaluation. Importantly, our engineered model and patient-derived cells reflect the complexity and heterogeneity of primary tumors, not observed with standard immortalized cell lines, offering a more clinically relevant system, although further validation is needed. High-throughput screening (HTS) of 4255 compounds identified 33 with selective efficacy against CRC cells, sparing normal, healthy epithelial cells. Among the tested combinations, everolimus (mTOR inhibitor) and uprosertib (AKT inhibitor) demonstrated promising synergy at clinically relevant concentrations, with favorable therapeutic windows confirmed across tested patient-derived cultures. Notably, this synergy, revealed through advanced models, might have been overlooked in traditional immortalized cell lines, highlighting the translational advantage of patient-derived systems. Furthermore, the integration of machine learning into the HTS pipeline significantly improved scalability, cost-efficiency, and predictive accuracy. Our findings underscore the potential of patient-derived materials combined with machine learning-enhanced drug discovery to advance personalized therapies. Specifically, mTOR-AKT inhibition emerges as a promising strategy for CRC treatment, paving the way for more effective and targeted therapeutic approaches. |
| format | Article |
| id | doaj-art-bc69b090faef47cab3295ed7913b386e |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-bc69b090faef47cab3295ed7913b386e2025-08-20T04:02:45ZengNature PortfolioScientific Reports2045-23222025-07-0115111710.1038/s41598-025-08649-0Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancerMarcin Duleba0Eliza Zimoląg1Joanna Szuszkiewicz2Marcin Serocki3Joanna Szklarczyk4Olga Dracz5Alexander Kurzejamski6Izabella Więckowska7Marcelina Chmiel8Barbara Lipert9Katarzyna Sarad10Joanna Krawczyk11Oleksii Bryzghalov12Agata Stachowicz-Wałaszek13Karolina Pyziak14Joanna Drozdowska15Krzysztof Baczyński16Konrad Wojtowicz17Maurycy Chronowski18Krzysztof Rataj19Magdalena Otrocka20Michał Mikula21Paula Feliksiak22Rafał Dziadziuszko23Tomasz Rzymski24Andrew Thomason25Krzysztof Brzózka26Andrzej Mazan27Ryvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsArdigenArdigenArdigenArdigenMaria Skłodowska-Curie National Research Institute of OncologyMedical University of GdańskMedical University of GdańskRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsRyvu TherapeuticsAbstract Colorectal cancer (CRC) treatment remains challenging due to genetic heterogeneity and resistance mechanisms. To address this, we developed a drug discovery pipeline using patient-derived primary CRC cultures with diverse genomic profiles. These cultures closely resemble certain molecular characteristics of primary and metastatic CRC, highlighting their promise as a translational platform for therapeutic evaluation. Importantly, our engineered model and patient-derived cells reflect the complexity and heterogeneity of primary tumors, not observed with standard immortalized cell lines, offering a more clinically relevant system, although further validation is needed. High-throughput screening (HTS) of 4255 compounds identified 33 with selective efficacy against CRC cells, sparing normal, healthy epithelial cells. Among the tested combinations, everolimus (mTOR inhibitor) and uprosertib (AKT inhibitor) demonstrated promising synergy at clinically relevant concentrations, with favorable therapeutic windows confirmed across tested patient-derived cultures. Notably, this synergy, revealed through advanced models, might have been overlooked in traditional immortalized cell lines, highlighting the translational advantage of patient-derived systems. Furthermore, the integration of machine learning into the HTS pipeline significantly improved scalability, cost-efficiency, and predictive accuracy. Our findings underscore the potential of patient-derived materials combined with machine learning-enhanced drug discovery to advance personalized therapies. Specifically, mTOR-AKT inhibition emerges as a promising strategy for CRC treatment, paving the way for more effective and targeted therapeutic approaches.https://doi.org/10.1038/s41598-025-08649-0 |
| spellingShingle | Marcin Duleba Eliza Zimoląg Joanna Szuszkiewicz Marcin Serocki Joanna Szklarczyk Olga Dracz Alexander Kurzejamski Izabella Więckowska Marcelina Chmiel Barbara Lipert Katarzyna Sarad Joanna Krawczyk Oleksii Bryzghalov Agata Stachowicz-Wałaszek Karolina Pyziak Joanna Drozdowska Krzysztof Baczyński Konrad Wojtowicz Maurycy Chronowski Krzysztof Rataj Magdalena Otrocka Michał Mikula Paula Feliksiak Rafał Dziadziuszko Tomasz Rzymski Andrew Thomason Krzysztof Brzózka Andrzej Mazan Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer Scientific Reports |
| title | Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer |
| title_full | Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer |
| title_fullStr | Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer |
| title_full_unstemmed | Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer |
| title_short | Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer |
| title_sort | integrated transcriptomic and functional modeling reveals akt and mtor synergy in colorectal cancer |
| url | https://doi.org/10.1038/s41598-025-08649-0 |
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