title: Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-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 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.
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Praveena S
authors.initials: PS
authors.lastname: Thiagarajan
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.|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.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wu
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Shi
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bagai
authors.affiliation: Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Leahy
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Veigl
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindner
authors.affiliation: Case Comprehensive Cancer Center, Cleveland, OH, USA.|Department of Pharmacology, and Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: David
authors.initials: D
authors.lastname: Danielpour
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Yin
authors.affiliation: Catalan Institute of Oncology, Badalona, Spain.|Spanish Lung Cancer Group, Badalona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.affiliation: Department of Medicine, Division of Hematology/ Oncology, Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|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.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019898:Autocrine Communication / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D059467:Transcriptome; D014162:Transfection; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047428:Protein Kinase Inhibitors; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; drug escape; inhibitor; lung cancer; resistance