Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies
Sophia A Wild1, Ian G Cannell1, Ashley Nicholls1
1Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, United Kingdom.
Abstract:
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.
Insights
Tumour heterogeneity poses a challenge in cancer treatment. Clonal transcriptomics identified NRF2-mediated oxidative stress as a taxane resistance mechanism, revealing asparagine deprivation as a potential therapy for resistant triple-negative breast cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Tumour heterogeneity complicates cancer treatment by fostering drug-resistant clones.
- Identifying the specific traits of these resistant lineages remains a significant challenge.
Purpose of the Study:
- To investigate mechanisms of therapy response and resistance in triple-negative breast cancer (TNBC) using clonal transcriptomics.
- To identify actionable vulnerabilities in drug-resistant tumour lineages.
Main Methods:
- Utilized Whole-genome sequencing for lineage dynamics (WILD-seq) in mouse models of TNBC.
- Analyzed response to BET bromodomain inhibition and taxane-based chemotherapy.
Main Results:
- Discovered NRF2-mediated oxidative stress protection as a key mechanism of taxane resistance.
- Identified collateral sensitivity to asparagine deprivation therapy (L-asparaginase) in docetaxel-resistant models.
Conclusions:
- Clonal transcriptomics with WILD-seq effectively identifies patient-relevant chemotherapy resistance mechanisms.
- Asparagine bioavailability represents a druggable vulnerability in taxane-resistant TNBC lineages.
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