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Identifying transcriptional programs underlying cancer drug response with TraCe-seq
Matthew T Chang1,2, Frances Shanahan2, Thi Thu Thao Nguyen1
1Department of Computational Biology and Bioinformatics, Genentech Inc., South San Francisco, CA, USA.
Nature Biotechnology
|September 17, 2021
Summary
A new method, TraCe-seq, tracks cancer cell responses to therapy at clonal resolution. Targeted EGFR degradation showed reduced anti-growth activity compared to kinase inhibitors in lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Cancer cell heterogeneity poses challenges for effective anticancer therapies.
- Current methods lack the robustness to assess how pre-existing and adaptive traits influence cellular drug responses.
Purpose of the Study:
- To develop a method for tracking differential clonal responses to cancer therapies at high resolution.
- To compare the efficacy of next-generation EGFR inhibitor-degraders versus standard EGFR kinase inhibitors in EGFR-mutant lung cancer.
Main Methods:
- Developed TraCe-seq (tracking differential clonal response by scRNA-seq), combining clonal fitness mapping and single-cell RNA sequencing (scRNA-seq) with expressed barcodes.
- Utilized TraCe-seq to analyze cellular origins, fates, and early adaptive transcriptional programs under distinct treatments.
- Benchmarked dual EGFR inhibitor-degraders against standard EGFR kinase inhibitors in EGFR-mutant lung cancer cells.
Main Results:
- Identified a loss of anti-growth activity with targeted epidermal growth factor receptor (EGFR) protein degradation.
- Revealed an essential role for the endoplasmic reticulum (ER) protein processing pathway in anti-EGFR therapeutic efficacy.
- Demonstrated that targeted degradation is not consistently superior to enzymatic inhibition.
Conclusions:
- TraCe-seq provides a powerful approach to study how pre-existing transcriptional programs influence treatment responses in cancer.
- Findings suggest a nuanced view on the efficacy of targeted protein degradation versus kinase inhibition for EGFR-mutant lung cancer.
- Highlights the importance of the ER protein processing pathway in mediating anti-EGFR therapy outcomes.
