Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer

EMBO Mol Med. 2018 Jun;10(6):e7945. doi: 10.15252/emmm.201707945.


Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR-mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small-cell lung cancer-associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non-druggable genetic information that may guide clinical management.

Keywords: circulating tumour DNA; liquid biopsy; lung cancer; resistance mechanisms; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • DNA, Neoplasm / blood
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / genetics
  • Gefitinib / therapeutic use*
  • Humans
  • Hydroxychloroquine / therapeutic use*
  • Longitudinal Studies
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mutation
  • Prognosis
  • Survival Analysis
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics


  • Antineoplastic Agents
  • DNA, Neoplasm
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Hydroxychloroquine
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib