PIK3CA mutation as an acquired resistance driver to EGFR-TKIs in non-small cell lung cancer: Clinical challenges and opportunities

Pharmacol Res. 2024 Apr:202:107123. doi: 10.1016/j.phrs.2024.107123. Epub 2024 Mar 2.

Abstract

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have significantly enhanced the treatment outcomes in non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, the occurrence of acquired resistance to EGFR-TKIs is an unavoidable outcome observed in these patients. Disruption of the PI3K/AKT/mTOR signaling pathway can contribute to the emergence of resistance to EGFR TKIs in lung cancer. The emergence of PIK3CA mutations following treatment with EGFR-TKIs can lead to resistance against EGFR-TKIs. This review provides an overview of the current perspectives regarding the involvement of PI3K/AKT/mTOR signaling in the development of lung cancer. Furthermore, we outline the state-of-the-art therapeutic strategies targeting the PI3K/AKT/mTOR signaling pathway in lung cancer. We highlight the role of PIK3CA mutation as an acquired resistance mechanism against EGFR-TKIs in EGFR-mutant NSCLC. Crucially, we explore therapeutic strategies targeting PIK3CA-mediated resistance to EGFR TKIs in lung cancer, aiming to optimize the effectiveness of treatment.

Keywords: Combined therapy; EGFR; Non-small cell lung cancer; PIK3CA; Resistance.

Publication types

  • Review

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Mutation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-akt / metabolism
  • TOR Serine-Threonine Kinases / genetics

Substances

  • Proto-Oncogene Proteins c-akt
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Protein Kinase Inhibitors
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • EGFR protein, human