Oncotarget

Priority Research Papers:

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

Praveena S. Thiagarajan, Xiaoliang Wu, Wei Zhang, Ivy Shi, Rakesh Bagai, Patrick Leahy, Yan Feng, Martina Veigl, Daniel Lindner, David Danielpour, Lihong Yin, Rafael Rosell, Trever G. Bivona, Zhenfeng Zhang and Patrick C. Ma _

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Oncotarget. 2016; 7:82013-82027. https://doi.org/10.18632/oncotarget.13307

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Abstract

Praveena S. Thiagarajan1,2,*, Xiaoliang Wu3,9,*, Wei Zhang1,9, Ivy Shi1, Rakesh Bagai1, Patrick Leahy4, Yan Feng1, Martina Veigl4, Daniel Lindner1,4, David Danielpour4,5, Lihong Yin1, Rafael Rosell6,7, Trever G. Bivona8, Zhenfeng Zhang3 and Patrick C. Ma1,2,9

1 Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

2 Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

4 Case Comprehensive Cancer Center, Cleveland, OH, USA

5 Department of Pharmacology, and Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA

6 Catalan Institute of Oncology, Badalona, Spain

7 Spanish Lung Cancer Group, Badalona, Spain

8 Department of Medicine, Division of Hematology/ Oncology, Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

9 Sara Crile Allen and James Frederick Allen Comprehensive Lung Cancer Program, Eminent Scholar in Lung Cancer Research, WVU Cancer Institute, West Virginia University, Morgantown, WV, USA

* These authors have contributed equally to this manuscript

Correspondence to:

Patrick C. Ma, email:

Keywords: EGFR; inhibitor; drug escape; resistance; lung cancer

Received: September 30, 2016 Accepted: October 28, 2016 Published: November 11, 2016

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 TGFβ2 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 TGFβ2 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.


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