Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug
Abstract It is increasingly suggested that ecological and evolutionary sciences could inspire novel therapies against cancer but medical evidence of this remains scarce at the moment. The Achilles heel of conventional and targeted anticancer treatments is intrinsic or acquired resistance following D...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Evolutionary Applications |
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| Online Access: | https://doi.org/10.1111/eva.12949 |
| _version_ | 1819082526777409536 |
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| author | Pierre‐Marie Girard Nathalie Berthault Maria Kozlac Sofia Ferreira Wael Jdey Srividya Bhaskara Sergey Alekseev Frederic Thomas Marie Dutreix |
| author_facet | Pierre‐Marie Girard Nathalie Berthault Maria Kozlac Sofia Ferreira Wael Jdey Srividya Bhaskara Sergey Alekseev Frederic Thomas Marie Dutreix |
| author_sort | Pierre‐Marie Girard |
| collection | DOAJ |
| description | Abstract It is increasingly suggested that ecological and evolutionary sciences could inspire novel therapies against cancer but medical evidence of this remains scarce at the moment. The Achilles heel of conventional and targeted anticancer treatments is intrinsic or acquired resistance following Darwinian selection; that is, treatment toxicity places the surviving cells under intense evolutionary selective pressure to develop resistance. Here, we review a set of data that demonstrate that Darwinian principles derived from the “smoke detector” principle can instead drive the evolution of malignant cells toward a different trajectory. Specifically, long‐term exposure of cancer cells to a strong alarm signal, generated by the DNA repair inhibitor AsiDNA, induces a stable new state characterized by a down‐regulation of the targeted pathways and does not generate resistant clones. This property is due to the original mechanism of action of AsiDNA, which acts by overactivating a “false” signaling of DNA damage through DNA‐PK and PARP enzymes, and is not observed with classical DNA repair inhibitors such as the PARP inhibitors. Long‐term treatment with AsiDNA induces a new “alarm down” state in the tumor cells with decrease in NAD level and reactiveness to it. These results suggest that agonist drugs such as AsiDNA could promote a state‐dependent tumor cell evolution by lowering their ability to respond to high “danger” signal. This analysis provides a compelling argument that evolutionary ecology could help drug design development in overcoming fundamental limitation of novel therapies against cancer due to the modification of the targeted tumor cell population during treatment. |
| first_indexed | 2024-12-21T20:18:05Z |
| format | Article |
| id | doaj.art-fba494f676724d71a6b72e1f42c09d2c |
| institution | Directory Open Access Journal |
| issn | 1752-4571 |
| language | English |
| last_indexed | 2024-12-21T20:18:05Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Evolutionary Applications |
| spelling | doaj.art-fba494f676724d71a6b72e1f42c09d2c2022-12-21T18:51:34ZengWileyEvolutionary Applications1752-45712020-08-011371673168010.1111/eva.12949Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drugPierre‐Marie Girard0Nathalie Berthault1Maria Kozlac2Sofia Ferreira3Wael Jdey4Srividya Bhaskara5Sergey Alekseev6Frederic Thomas7Marie Dutreix8Institut Curie CNRS INSERM UMR 3347 PSL Research University Orsay FranceInstitut Curie CNRS INSERM UMR 3347 PSL Research University Orsay FranceInstitut Curie CNRS INSERM UMR 3347 PSL Research University Orsay FranceInstitut Curie CNRS INSERM UMR 3347 PSL Research University Orsay FranceInstitut Curie CNRS INSERM UMR 3347 PSL Research University Orsay FranceHuntsman Cancer Institute University of Utah School of Medicine Salt Lake City Utah USAInstitut Curie CNRS INSERM UMR 3347 PSL Research University Orsay FranceCREEC/MIVEGEC UMR IRD 224‐CNRS 5290 Université de Montpellier Montpellier FranceInstitut Curie CNRS INSERM UMR 3347 PSL Research University Orsay FranceAbstract It is increasingly suggested that ecological and evolutionary sciences could inspire novel therapies against cancer but medical evidence of this remains scarce at the moment. The Achilles heel of conventional and targeted anticancer treatments is intrinsic or acquired resistance following Darwinian selection; that is, treatment toxicity places the surviving cells under intense evolutionary selective pressure to develop resistance. Here, we review a set of data that demonstrate that Darwinian principles derived from the “smoke detector” principle can instead drive the evolution of malignant cells toward a different trajectory. Specifically, long‐term exposure of cancer cells to a strong alarm signal, generated by the DNA repair inhibitor AsiDNA, induces a stable new state characterized by a down‐regulation of the targeted pathways and does not generate resistant clones. This property is due to the original mechanism of action of AsiDNA, which acts by overactivating a “false” signaling of DNA damage through DNA‐PK and PARP enzymes, and is not observed with classical DNA repair inhibitors such as the PARP inhibitors. Long‐term treatment with AsiDNA induces a new “alarm down” state in the tumor cells with decrease in NAD level and reactiveness to it. These results suggest that agonist drugs such as AsiDNA could promote a state‐dependent tumor cell evolution by lowering their ability to respond to high “danger” signal. This analysis provides a compelling argument that evolutionary ecology could help drug design development in overcoming fundamental limitation of novel therapies against cancer due to the modification of the targeted tumor cell population during treatment.https://doi.org/10.1111/eva.12949biomedicinedisease biologyevolutionary theorytranscriptomics |
| spellingShingle | Pierre‐Marie Girard Nathalie Berthault Maria Kozlac Sofia Ferreira Wael Jdey Srividya Bhaskara Sergey Alekseev Frederic Thomas Marie Dutreix Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug Evolutionary Applications biomedicine disease biology evolutionary theory transcriptomics |
| title | Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug |
| title_full | Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug |
| title_fullStr | Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug |
| title_full_unstemmed | Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug |
| title_short | Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug |
| title_sort | evolution of tumor cells during asidna treatment results in energy exhaustion decrease in responsiveness to signal and higher sensitivity to the drug |
| topic | biomedicine disease biology evolutionary theory transcriptomics |
| url | https://doi.org/10.1111/eva.12949 |
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