Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer

J Thorac Oncol. 2011 Apr;6(4):707-15. doi: 10.1097/JTO.0b013e31820a3a6b.


Background: Specific mutations of the epidermal growth factor receptor (EGFR) gene are predictive for favorable response to tyrosine kinase inhibitors (TKIs) and are associated with a good prognosis. In contrast, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation has been shown to predict poor response to such therapy. Nevertheless, tumor that initially responds to EGFR-TKIs almost inevitably becomes resistant later. Other mechanisms of resistance to EGFR inhibitors could involve activating mutations of the other main EGFR effector pathway, i.e., the phosphoinositide-3-kinase/phosphate and tensin homologue deleted from chromosome 10 (PTEN)/alpha serine/threonine protein kinase (AKT) pathway. The aim of this study was to investigate the role of phosphoinositide-3-kinase catalytic alpha (PIK3CA), EGFR, and KRAS gene mutations in predicting response and survival in patients with non-small cell lung cancer (NSCLC) treated with EGFR-TKIs.

Patients and methods: A total of 166 patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. PIK3CA, EGFR, and KRAS mutations were analyzed using polymerase chain reaction-based sequencing.

Results: EGFR mutation was detected in 25.3% of patients, PIK3CA mutation in 4.1%, and KRAS mutation in 6.7%. PIK3CA mutation correlated with shorter median time to progression (TTP) (p = 0.01) and worse overall survival (OS) (p < 0.001). EGFR mutation (p < 0.0001) correlated with favorable response to TKIs treatment and longer TTP (p < 0.0001). KRAS mutation correlated with progressive disease (p = 0.05) and shorter median TTP (p = 0.003) but not with OS. Cox multivariate analysis including histology and performance status showed that PIK3CA mutation was an independent factor to predict worse OS (p = 0.0001) and shorter TTP (p = 0.03), while KRAS mutation to predict shorter TTP (p = 0.01).

Conclusion: PIK3CA and KRAS mutations seem to be indicators of resistance and poor survival in patients with NSCLC treated with EGFR-TKIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / secondary
  • Adenocarcinoma, Bronchiolo-Alveolar / drug therapy
  • Adenocarcinoma, Bronchiolo-Alveolar / genetics
  • Adenocarcinoma, Bronchiolo-Alveolar / secondary
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Large Cell / drug therapy
  • Carcinoma, Large Cell / genetics
  • Carcinoma, Large Cell / secondary
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / secondary
  • Class I Phosphatidylinositol 3-Kinases
  • DNA, Neoplasm / genetics
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / genetics*
  • Female
  • Follow-Up Studies
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation / genetics*
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / genetics*
  • Polymerase Chain Reaction
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Retrospective Studies
  • Survival Rate
  • ras Proteins / genetics


  • DNA, Neoplasm
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • EGFR protein, human
  • ErbB Receptors
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins