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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking

Praveena S Thiagarajan1,2, Xiaoliang Wu3,4, Wei Zhang1,4

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

Oncotarget
|November 17, 2016
PubMed

Insights

Early adaptive resistance to EGFR precision therapy in non-small cell lung cancer (NSCLC) involves MET-independent TGFβ2 signaling. Targeting bioenergetics and mitochondrial priming with combined EGFR inhibitors and BH3-mimetics can overcome this early drug escape.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Acquired resistance limits the efficacy of EGFR-mutant non-small cell lung cancer (NSCLC) precision therapy.
  • Previous resistance studies focused on late-stage tumor progression, missing early adaptive mechanisms.

Purpose of the Study:

  • To characterize a novel, MET-independent, non-mutational early adaptive drug-escape mechanism in EGFR-mutant NSCLC cells.
  • To identify the molecular drivers and vulnerabilities of this early adaptive resistance.

Main Methods:

  • Integrated transcriptomic and metabolomics profiling of EGFR-mutant lung tumor cells.
  • Analysis of cellular plasticity, metabolic reprogramming, and signaling pathways involved in drug escape.

Main Results:

  • A novel early adaptive drug-escape mechanism was identified, occurring days after therapy initiation and independent of MET.
  • Autocrine TGFβ2 signaling drives cellular plasticity and adaptive reprogramming, linked to mitochondrial priming.
  • Drug-escaped cells exhibit metabolic quiescence, enhanced EMT-ness, stem cell signaling, and suppressed bioenergetics (including reverse Warburg effect).
  • These cells are sensitive to glutamine deprivation and TGFβ2 inhibition.

Conclusions:

  • Early adaptive drug escape in EGFR-mutant NSCLC is mediated by TGFβ2-driven cellular plasticity and mitochondrial priming.
  • Preemptive therapeutic strategies targeting bioenergetics and mitochondrial priming are crucial.
  • Combining EGFR precision inhibitors with broad BH3-mimetics (targeting BCL-2/BCL-xL) shows promise in overcoming early drug escape, unlike BCL-2 inhibitors alone.
Keywords:
EGFRdrug escapeinhibitorlung cancerresistance

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