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Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition

GSE75602 Homo sapiens Expression profiling by high throughput sequencing 22 samples Submitted 2016/02/01 Platform GPL16791
Summary
Although mechanisms of acquired resistance of EGFR mutant non-small cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here, we observe that acquired resistance caused by the T790M gatekeeper mutation can occur either by selection of pre-existing T790M clones or via genetic evolution of initially T790M-negative drug tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug tolerant cells had a diminished apoptotic response to third generation EGFR inhibitors that target T790M EGFR; treatment with navitoclax, an inhibitor of BCL-XL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug resistant cancer cells can both pre-exist and evolve from drug tolerant cells, and point to therapeutic opportunities to prevent or overcome resistance in the clinic.
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Direct links to NCBI, no account and no request form: the whole study as GSE75602_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 22 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA304927 and SRA study SRP066956. Searching any of these in the dataset finder brings you back here.

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