Dataset Information

Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGF?2-bioenergetics-mitochondrial priming.

ABSTRACT: The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGF?2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming. Cells undergoing early adaptive drug escape are in proliferative-metabolic quiescent, with enhanced EMT-ness and stem cell signaling, exhibiting global bioenergetics suppression including reverse Warburg, and are susceptible to glutamine deprivation and TGF?2 inhibition. Our study further supports a preemptive therapeutic targeting of bioenergetics and mitochondrial priming to impact early drug-escape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone.

SUBMITTER: Thiagarajan PS

PROVIDER: S-EPMC5347670 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming.

Thiagarajan Praveena S PS Wu Xiaoliang X Zhang Wei W Shi Ivy I Bagai Rakesh R Leahy Patrick P Feng Yan Y Veigl Martina M Lindner Daniel D Danielpour David D Yin Lihong L Rosell Rafael R Bivona Trever G TG Zhang Zhenfeng Z Ma Patrick C PC

Oncotarget 20161201 50

The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated tran ...[more]

PMID: 27852038

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Dataset Information

Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGF?2-bioenergetics-mitochondrial priming.

Publications

Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming.

Similar Datasets

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