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Updated: Apr 10, 2026

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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EGFR inhibitor and chemotherapy combinations for acquired TKI resistance in EGFR-mutant NSCLC models

Niina Laurila1, Jussi P Koivunen

  • 1Department of Medical Oncology and Radiotherapy, Oulu University Hospital, PB22, 90029, Oulu, Finland.

Medical Oncology (Northwood, London, England)
|June 18, 2015
PubMed

Insights

Combining chemotherapy with EGFR TKIs shows synergistic effects against acquired resistance in non-small cell lung cancer (NSCLC). Chemotherapy preceding or concurrent with EGFR TKIs is more effective than the reverse sequence.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Acquired resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) limits treatment efficacy in EGFR-mutant Non-Small Cell Lung Cancer (NSCLC).
  • The optimal sequence for combining EGFR TKIs with chemotherapy in acquired resistance settings remains undetermined.

Purpose of the Study:

  • To investigate the efficacy of combining EGFR TKIs with chemotherapy in preclinical models of acquired EGFR TKI resistance in NSCLC.
  • To determine the optimal sequence of administration for EGFR TKIs and chemotherapy.

Main Methods:

  • Utilized NSCLC cell lines (PC9ER, H1975, HCC827GR) with acquired TKI resistance genotypes (T790M, cMET).
  • Exposed cells to chemotherapeutic agents (cisplatin, paclitaxel) in combination with EGFR TKIs (erlotinib, WZ4002) in vitro.
  • Assessed cytotoxicity and apoptotic response to evaluate treatment efficacy and sequence-dependent effects.

Main Results:

  • All tested combinations of EGFR TKIs and chemotherapy demonstrated synergistic effects on cytotoxicity.
  • Combinations significantly increased the apoptotic response in resistant NSCLC cells.
  • Sequences involving concurrent or preceding chemotherapy administration were more effective than sequential EGFR TKI followed by chemotherapy.

Conclusions:

  • Combination therapy of EGFR TKIs and chemotherapy is beneficial for acquired EGFR TKI resistance in NSCLC.
  • Chemotherapy followed by EGFR TKI administration (intercalated approach) appears to be the most potent strategy.
  • This intercalated strategy warrants further investigation in randomized clinical trials.

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