Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer

Sci Transl Med. 2019 Sep 18;11(510):eaaw7999. doi: 10.1126/scitranslmed.aaw7999.

Abstract

KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype. Combined mTOR, IGF1R, and MEK inhibition inhibits the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacing the MEK inhibitor with the mutant-specific KRAS-G12C inhibitor ARS-1620 in these combinations is associated with greater efficacy, specificity, and tolerability. Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Survival / drug effects
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mutation / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use
  • Pyridones / pharmacology
  • Pyridones / therapeutic use
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use
  • RNA, Small Interfering / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyridones
  • Pyrimidinones
  • RNA, Small Interfering
  • trametinib
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)