Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer

Cancer Lett. 2024 Aug 28:598:217124. doi: 10.1016/j.canlet.2024.217124. Epub 2024 Jul 24.

Abstract

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.

Keywords: AXL; EGFR mutation; FGF2; FGFR1; Non-small-cell lung cancer.

MeSH terms

  • Acrylamides* / pharmacology
  • Aniline Compounds* / pharmacology
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Apoptosis / drug effects
  • Axl Receptor Tyrosine Kinase*
  • Benzocycloheptenes
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • ErbB Receptors* / antagonists & inhibitors
  • ErbB Receptors* / genetics
  • Female
  • Humans
  • Indoles
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacology
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins* / antagonists & inhibitors
  • Proto-Oncogene Proteins* / genetics
  • Proto-Oncogene Proteins* / metabolism
  • Pyrimidines* / pharmacology
  • Receptor Protein-Tyrosine Kinases* / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases* / genetics
  • Receptor, Fibroblast Growth Factor, Type 1* / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 1* / genetics
  • Receptor, Fibroblast Growth Factor, Type 1* / metabolism
  • Triazoles
  • Xenograft Model Antitumor Assays

Substances

  • Acrylamides
  • Aniline Compounds
  • AXL protein, human
  • Axl Receptor Tyrosine Kinase
  • bemcentinib
  • Benzocycloheptenes
  • EGFR protein, human
  • ErbB Receptors
  • FGFR1 protein, human
  • Indoles
  • infigratinib
  • osimertinib
  • Phenylurea Compounds
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrimidines
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Triazoles