Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer

J Exp Clin Cancer Res. 2023 Jan 30;42(1):37. doi: 10.1186/s13046-023-02606-3.

Abstract

Background: A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer.

Methods: Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles.

Results: PDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-β expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-β-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939.

Conclusions: Our PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.

Keywords: EGFR-TKI; Osimertinib resistance; Patient-derived cell; Pharmacogenomics; Small-cell lung cancer; YAP/TAZ-AXL axis.

MeSH terms

  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Mutation
  • Pharmacogenetics*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use

Substances

  • osimertinib
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Protein Kinase Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors