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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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Mechanisms of acquired resistance to afatinib clarified with liquid biopsy

Tomomi Nakamura1, Chiho Nakashima1, Kazutoshi Komiya1

  • 1Department of Internal Medicine, Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.

Plos One
|December 15, 2018
PubMed

Insights

Acquired resistance to afatinib in lung cancer is often linked to EGFR T790M mutations. The C797S mutation also appears post-treatment, potentially impacting progression-free survival with subsequent therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are crucial for optimizing lung cancer treatment.
  • While resistance to 1st and 3rd generation EGFR-TKIs is well-studied, investigations into resistance to the 2nd generation EGFR-TKI afatinib are limited.

Purpose of the Study:

  • To investigate the molecular mechanisms of acquired resistance to afatinib in patients with advanced lung adenocarcinoma.
  • To analyze the prevalence and impact of key resistance mutations, including EGFR T790M and C797S, BRAF V600E, and MET amplification.

Main Methods:

  • Analysis of clinical data from 20 patients with advanced lung adenocarcinoma who developed resistance to afatinib.
  • Detection of EGFR T790M, C797S, BRAF V600E mutations, and MET amplification using MBP-QP and droplet digital PCR on ctDNA and re-biopsy samples.
  • Assessment of mutation status before and after afatinib treatment.

Main Results:

  • EGFR T790M mutation was associated with acquired resistance to afatinib, detected in 40% of initially T790M-negative patients at progression.
  • Changes in T790M allele frequency correlated with afatinib treatment efficacy.
  • C797S mutation appeared post-treatment in three patients, with two achieving partial response to osimertinib, but exhibiting shorter progression-free survival compared to T790M-only patients.
  • BRAF V600E was detected in one patient; MET amplification was not observed.

Conclusions:

  • EGFR T790M is a significant mechanism of acquired resistance to afatinib, similar to 1st generation EGFR-TKIs, though observed at a lower frequency.
  • The C797S mutation, while less frequent, may influence resistance to afatinib and potentially lead to shorter progression-free survival under osimertinib treatment.
  • Further research is needed to fully elucidate the role of C797S in afatinib resistance and subsequent treatment outcomes.

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