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.
Highlights
EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib are approved precision therapies for advanced non-small cell lung cancer (NSCLC) treatment in patients with drug-sensitizing EGFR-mutant tumors [1,2,3]
Our results showed that within the drug escape process, there is a link between TGFβ2 and adaptive global cellular reprogramming involving bioenergeticsmitochondrial BCL-2/BCL-xL cascades to promote a prosurvival cell state embedded in the proliferativemetabolic quiescence
Our current study results notably identified a novel adaptive metabolomic reprogramming under molecularly targeted therapeutics stress resulting in globally suppressed cellular metabolism including glycolytic pathway, tricarboxylic acid (TCA) cycle pathway, branched chain amino acids metabolism, lipid biogenesis, and enhanced inflammatory metabolism, in an overall effort to promote tumor cells survival and therapeutic escape
Summary
EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib are approved precision therapies for advanced non-small cell lung cancer (NSCLC) treatment in patients with drug-sensitizing EGFR-mutant tumors [1,2,3]. Emphasizing on early changes of EGFR/MET inhibitors on drug-sensitive lung tumor cells [13], we have recently identified and characterized the early onset adaptive precision drug escape that emerged from the treated drug-sensitive parental cell population, after TKI exposure for as short as merely 6-9 days. These cells in drug escape exhibited ~100-fold higher drug-resistance phenotype, and a METindependent but enhanced dependence on the intrinsic mitochondrial prosurvival signaling cascade [13]. Our study showed that while undergoing drug escape, these cells had profoundly inhibited adaptive state of proliferation, cell motility and migration (http://cancerres. aacrjournals.org/content/71/13/4494/ suppl/DC1)
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