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Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
Heathcliff Dorado García1,2,3, Fabian Pusch1, Yi Bei1,2,3
1Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany.
Abstract:
Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.
Insights
Alveolar rhabdomyosarcoma (ARMS) cells expressing PAX3-FOXO1 are sensitive to ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Combining ATR and PARP1 inhibitors promotes complete tumor regression in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Alveolar rhabdomyosarcoma (ARMS) driven by the PAX3-FOXO1 fusion oncogene has poor clinical outcomes.
- Current multi-modal treatments offer limited efficacy for ARMS patients.
Purpose of the Study:
- To investigate the therapeutic potential of targeting the DNA damage response in ARMS.
- To identify novel therapeutic strategies and resistance mechanisms in PAX3-FOXO1-driven ARMS.
Main Methods:
- Assessed sensitivity of ARMS cells to ataxia telangiectasia and Rad3 related protein (ATR) inhibitors.
- Investigated the impact of ATR inhibition on DNA repair pathways, including homologous recombination.
- Utilized a genome-wide CRISPR activation screen to identify resistance mechanisms.
- Evaluated combined ATR and PARP1 inhibition in patient-derived xenografts.
Main Results:
- PAX3-FOXO1-expressing ARMS cells demonstrate sensitivity to ATR inhibition.
- ATR inhibition exacerbates replication stress and impairs homologous recombination DNA repair.
- Combined ATR and PARP1 inhibition achieved complete regression of ARMS xenografts.
- The RAS-MAPK pathway and FOS genes were identified as mediators of resistance to ATR inhibition.
Conclusions:
- Pharmacological ATR inhibition is a promising therapeutic strategy for ARMS.
- Combination therapy with ATR and PARP1 inhibitors offers a potent treatment approach for ARMS.
- Understanding resistance mechanisms involving the RAS-MAPK pathway is crucial for optimizing ATR inhibitor efficacy in ARMS treatment.
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