Early tolerance and late persistence as alternative drug responses in cancer
Abstract Bacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elic...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54728-7 |
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| author | Simona Punzi Davide Cittaro Guido Gatti Gemma Crupi Oronza A. Botrugno Antonino Alex Cartalemi Alon Gutfreund Caterina Oneto Valentina Giansanti Chiara Battistini Giovanni Santacatterina Lucrezia Patruno Ilaria Villanti Martina Palumbo Daniel J. Laverty Francesca Giannese Alex Graudenzi Giulio Caravagna Marco Antoniotti Zachary Nagel Ugo Cavallaro Luisa Lanfrancone Timothy A. Yap Giulio Draetta Nathalie Balaban Giovanni Tonon |
| author_facet | Simona Punzi Davide Cittaro Guido Gatti Gemma Crupi Oronza A. Botrugno Antonino Alex Cartalemi Alon Gutfreund Caterina Oneto Valentina Giansanti Chiara Battistini Giovanni Santacatterina Lucrezia Patruno Ilaria Villanti Martina Palumbo Daniel J. Laverty Francesca Giannese Alex Graudenzi Giulio Caravagna Marco Antoniotti Zachary Nagel Ugo Cavallaro Luisa Lanfrancone Timothy A. Yap Giulio Draetta Nathalie Balaban Giovanni Tonon |
| author_sort | Simona Punzi |
| collection | DOAJ |
| description | Abstract Bacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elicit a tolerant response when exposed to commonly used chemotherapy regimens, propelled by the pervasive activation of autophagy, leading to the comprehensive activation of DNA damage repair pathways. After prolonged drug exposure, such tolerant responses morph into persistence, whereby the increased DNA damage repair is entirely reversed. The central regulator of mitophagy PINK1 drives this reduction in DNA repair via the cytoplasmic relocalization of the cell identity master HNF4A, thus hampering HNF4A transcriptional activation of DNA repair genes. We conclude that exposing cancer cells to relevant standard-of-care antitumour therapies induces a pervasive drug-induced tolerant response that might be broadly exploited to increase the impact of first-line, adjuvant treatments and debulking in advanced cancers. |
| format | Article |
| id | doaj-art-2e879c921fb54ca1b61d1c377955d8bc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2e879c921fb54ca1b61d1c377955d8bc2025-02-09T12:44:44ZengNature PortfolioNature Communications2041-17232025-02-0116111810.1038/s41467-024-54728-7Early tolerance and late persistence as alternative drug responses in cancerSimona Punzi0Davide Cittaro1Guido Gatti2Gemma Crupi3Oronza A. Botrugno4Antonino Alex Cartalemi5Alon Gutfreund6Caterina Oneto7Valentina Giansanti8Chiara Battistini9Giovanni Santacatterina10Lucrezia Patruno11Ilaria Villanti12Martina Palumbo13Daniel J. Laverty14Francesca Giannese15Alex Graudenzi16Giulio Caravagna17Marco Antoniotti18Zachary Nagel19Ugo Cavallaro20Luisa Lanfrancone21Timothy A. Yap22Giulio Draetta23Nathalie Balaban24Giovanni Tonon25Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteCenter for Omics Sciences, IRCCS San Raffaele Scientific InstituteFunctional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteFunctional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteFunctional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteFunctional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteThe Racah Institute of Physics, The Hebrew University of JerusalemCenter for Omics Sciences, IRCCS San Raffaele Scientific InstituteCenter for Omics Sciences, IRCCS San Raffaele Scientific InstituteUnit of Gynaecological Oncology Research, European Institute of Oncology IRCSSCancer Data Science Laboratory, Department of Mathematics and Geosciences, University of TriesteDepartment of Informatics, Systems and Communication of the University of Milan-BicoccaUniversità Vita-Salute San RaffaeleFunctional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteHarvard Chan School of Public HealthCenter for Omics Sciences, IRCCS San Raffaele Scientific InstituteDepartment of Informatics, Systems and Communication of the University of Milan-BicoccaCancer Data Science Laboratory, Department of Mathematics and Geosciences, University of TriesteDepartment of Informatics, Systems and Communication of the University of Milan-BicoccaHarvard Chan School of Public HealthUnit of Gynaecological Oncology Research, European Institute of Oncology IRCSSDepartment of Experimental Oncology, European Institute of Oncology IRCCSTherapeutics Discovery Division, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center HoustonThe Racah Institute of Physics, The Hebrew University of JerusalemFunctional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific InstituteAbstract Bacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elicit a tolerant response when exposed to commonly used chemotherapy regimens, propelled by the pervasive activation of autophagy, leading to the comprehensive activation of DNA damage repair pathways. After prolonged drug exposure, such tolerant responses morph into persistence, whereby the increased DNA damage repair is entirely reversed. The central regulator of mitophagy PINK1 drives this reduction in DNA repair via the cytoplasmic relocalization of the cell identity master HNF4A, thus hampering HNF4A transcriptional activation of DNA repair genes. We conclude that exposing cancer cells to relevant standard-of-care antitumour therapies induces a pervasive drug-induced tolerant response that might be broadly exploited to increase the impact of first-line, adjuvant treatments and debulking in advanced cancers.https://doi.org/10.1038/s41467-024-54728-7 |
| spellingShingle | Simona Punzi Davide Cittaro Guido Gatti Gemma Crupi Oronza A. Botrugno Antonino Alex Cartalemi Alon Gutfreund Caterina Oneto Valentina Giansanti Chiara Battistini Giovanni Santacatterina Lucrezia Patruno Ilaria Villanti Martina Palumbo Daniel J. Laverty Francesca Giannese Alex Graudenzi Giulio Caravagna Marco Antoniotti Zachary Nagel Ugo Cavallaro Luisa Lanfrancone Timothy A. Yap Giulio Draetta Nathalie Balaban Giovanni Tonon Early tolerance and late persistence as alternative drug responses in cancer Nature Communications |
| title | Early tolerance and late persistence as alternative drug responses in cancer |
| title_full | Early tolerance and late persistence as alternative drug responses in cancer |
| title_fullStr | Early tolerance and late persistence as alternative drug responses in cancer |
| title_full_unstemmed | Early tolerance and late persistence as alternative drug responses in cancer |
| title_short | Early tolerance and late persistence as alternative drug responses in cancer |
| title_sort | early tolerance and late persistence as alternative drug responses in cancer |
| url | https://doi.org/10.1038/s41467-024-54728-7 |
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