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Assessing signaling pathways associated with in vitro resistance to cytotoxic agents in AML
David B Rosen1, James A Cordeiro, Aileen Cohen
1Department of Research, Nodality Inc, South San Francisco, CA, United States.
Abstract:
This study uses single cell network profiling (SCNP) to characterize biological pathways associated with in vitro resistance or sensitivity to chemotherapeutics commonly used in acute myeloid leukemia (AML) (i.e. cytarabine/daunorubicin, gemtuzumab ozogamicin (GO), decitabine, azacitidine, clofarabine). Simultaneous measurements at the single cell level of changes in DNA damage, apoptosis and signaling pathway responses in AML blasts incubated in vitro with the above drugs showed distinct profiles for each sample and mechanistically different profiles between distinct classes of agents. Studies are ongoing to assess the clinical predictive value of these findings.
Insights
Single cell network profiling reveals distinct biological pathway responses to acute myeloid leukemia (AML) chemotherapy agents. These findings may predict patient response to AML treatments.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Acute Myeloid Leukemia (AML) treatment relies on chemotherapy with varying efficacy.
- Understanding cellular mechanisms of drug resistance and sensitivity is crucial for improving AML therapy.
- Single-cell analysis offers a powerful approach to dissect cellular heterogeneity in response to treatment.
Purpose of the Study:
- To characterize the biological pathways involved in chemoresistance and chemosensitivity in AML.
- To differentiate the cellular responses to various AML chemotherapeutic agents using a high-throughput single-cell method.
- To explore the potential of single-cell profiling for predicting clinical outcomes in AML.
Main Methods:
- Utilized Single Cell Network Profiling (SCNP) to analyze AML blasts.
- Incubated AML cells in vitro with common chemotherapeutics: cytarabine/daunorubicin, gemtuzumab ozogamicin (GO), decitabine, azacitidine, and clofarabine.
- Simultaneously measured DNA damage, apoptosis, and signaling pathway activation at the single-cell level.
Main Results:
- Observed distinct SCNP profiles for each AML sample.
- Identified mechanistically different pathway profiles between distinct classes of chemotherapeutic agents.
- Demonstrated that SCNP can capture nuanced cellular responses to AML drugs.
Conclusions:
- SCNP provides a detailed molecular portrait of AML cell responses to chemotherapy.
- The distinct profiles suggest potential biomarkers for drug sensitivity or resistance in AML.
- Further studies are warranted to validate the clinical predictive value of these SCNP findings for AML patients.
