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.

AXL–GAS6 expression can predict for adverse prognosis in non-small cell lung cancer with brain metastases

“…Previous studies reported by our group demonstrated that acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant EGFR-mutant NSCLC cells not only overexpressed AXL, but also demonstrated a concomitant EMT-associated transcriptional program involving upregulation of vimentin (Zhang et al 2012 ). Our recent studies also supported the notion that early adaptive precision drug-resistant escape in EGFR-mutant NSCLC under EGFR inhibitor treatment is associated with a quiescence cell state under transcriptomic-metabolomic cellular reprogramming that has an enhanced EMT-ness, cancer stemness, and upregulated vimentin (Thiagarajan et al 2016 ). The EMT signature and AXL might be predictive biomarkers of drug response-resistance profile and therapeutic targets in patients with NSCLC (Fischer et al 2015 ; Thiagarajan et al 2016 ; Wu et al 2014a ).…”

“…Our recent studies also supported the notion that early adaptive precision drug-resistant escape in EGFR-mutant NSCLC under EGFR inhibitor treatment is associated with a quiescence cell state under transcriptomic-metabolomic cellular reprogramming that has an enhanced EMT-ness, cancer stemness, and upregulated vimentin (Thiagarajan et al 2016 ). The EMT signature and AXL might be predictive biomarkers of drug response-resistance profile and therapeutic targets in patients with NSCLC (Fischer et al 2015 ; Thiagarajan et al 2016 ; Wu et al 2014a ). As overexpression of AXL/GAS6 can contribute to tumor invasion, metastasis especially to the brain, and drug resistance against chemotherapy and targeted therapies in NSCLC, the AXL/GAS6 pathway can be promising therapeutic target for clinical inhibition.…”

Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase

“…Metabolic and transcriptional profiling revealed downregulation of pyruvate dehydrogenase kinase 4 (PDK4) contributes to a glycolysis to oxidative phosphorylation (OXPHOS) shift, causing EMT and promoting acquired resistance to erlotinib in EGFR mutant lung cancer cells 23 . Thiagarajan et al reported that 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 effect 24 .…”

Combined Inhibitions of Glycolysis and AKT/autophagy Can Overcome Resistance to EGFR-targeted Therapy of Lung Cancer

“…Another study showed that resistance to a TKI-axitinib is associated with increased glucose metabolism in pancreatic adenocarcinoma 14 . We have recently explored transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug resistance and showed the early adaptive drug escape linked TGFβ2-bioenergetics-mitochondrial priming 15 . We have successfully established a series of erlotinib-resistant subclonal cells (ER1-6) originated from HCC827 cells through de-sensitizing the HCC827 cells in gradually increasing erlotinib concentrations until 10μM in the culture media, and reported AXL kinase as a novel resistance molecule in ER1-5 cells 4 .…”