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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS

Catherine A Eberlein1, Daniel Stetson2, Aleksandra A Markovets2

  • 1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.

Cancer Research
|April 15, 2015
PubMed

Insights

Resistance to EGFR inhibitors in lung cancer can be overcome by combining EGFR inhibitors with MEK inhibitors. This combination therapy, particularly AZD9291 and selumetinib, prevents or delays resistance and can even cause tumor regression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a significant challenge in treating EGFR-mutant lung cancers.
  • Identifying resistance mechanisms is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate heterogeneous resistance mechanisms to EGFR inhibitors in EGFR-mutant lung cancer cells.
  • To evaluate the efficacy of combining EGFR inhibitors with MEK inhibitors in overcoming acquired resistance.

Main Methods:

  • Utilized EGFR-mutant lung cancer cell lines (PC9, NCI-H1975) with acquired resistance to various EGFR TKIs, including AZD9291.
  • Analyzed resistance mechanisms, including NRAS mutations and copy number gains.
  • Assessed the in vitro and in vivo efficacy of combination therapy with EGFR inhibitors (AZD9291) and MEK inhibitors (selumetinib).

Main Results:

  • Detected NRAS mutations (including novel E63K) and copy number gains of WT NRAS/KRAS in resistant cell populations.
  • Resistant cells showed increased sensitivity to MEK inhibitor selumetinib when combined with EGFR inhibitors.
  • Combination of AZD9291 and selumetinib prevented or delayed resistance in vitro and caused regression of resistant tumors in vivo.

Conclusions:

  • Combination therapy with AZD9291 and selumetinib is a promising strategy to delay or prevent resistance in EGFR-mutant and EGFRm/T790M lung tumors.
  • NRAS alterations in patients progressing on EGFR inhibitors may indicate suitability for combined EGFR and MEK inhibition therapy.

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