Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies
© 2022, Wild, Cannell et al..
Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilise clonal transcriptomics with WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, in mouse models of triple-negative breast cancer (TNBC) to understand response and resistance to therapy, including BET bromodomain inhibition and taxane-based chemotherapy. These analyses revealed oxidative stress protection by NRF2 as a major mechanism of taxane resistance and led to the discovery that our tumour models are collaterally sensitive to asparagine deprivation therapy using the clinical stage drug L-asparaginase after frontline treatment with docetaxel. In summary, clonal transcriptomics with WILD-seq identifies mechanisms of resistance to chemotherapy that are also operative in patients and pin points asparagine bioavailability as a druggable vulnerability of taxane-resistant lineages.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
eLife - 11(2022) vom: 16. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wild, Sophia A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.12.2022 Date Revised 23.02.2024 published: Electronic GEO: GSE218774, GSE28844 Citation Status MEDLINE |
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| doi: |
10.7554/eLife.80981 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Wild, Sophia A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 20.12.2022 | ||
| 500 | |a Date Revised 23.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a GEO: GSE218774, GSE28844 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022, Wild, Cannell et al. | ||
| 520 | |a Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilise clonal transcriptomics with WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, in mouse models of triple-negative breast cancer (TNBC) to understand response and resistance to therapy, including BET bromodomain inhibition and taxane-based chemotherapy. These analyses revealed oxidative stress protection by NRF2 as a major mechanism of taxane resistance and led to the discovery that our tumour models are collaterally sensitive to asparagine deprivation therapy using the clinical stage drug L-asparaginase after frontline treatment with docetaxel. In summary, clonal transcriptomics with WILD-seq identifies mechanisms of resistance to chemotherapy that are also operative in patients and pin points asparagine bioavailability as a druggable vulnerability of taxane-resistant lineages | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cancer biology | |
| 650 | 4 | |a cancer therapy | |
| 650 | 4 | |a chromosomes | |
| 650 | 4 | |a gene expression | |
| 650 | 4 | |a lineage tracing | |
| 650 | 4 | |a mouse | |
| 650 | 4 | |a single cell genomics | |
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| 700 | 1 | |a Bressan, Dario |e verfasserin |4 aut | |
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