A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance

Nat Cancer. 2024 Aug;5(8):1250-1266. doi: 10.1038/s43018-024-00781-6. Epub 2024 Jul 11.

Abstract

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy
  • Drug Resistance, Neoplasm* / drug effects
  • ErbB Receptors* / antagonists & inhibitors
  • ErbB Receptors* / metabolism
  • Female
  • Head and Neck Neoplasms / drug therapy
  • Humans
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors / therapeutic use
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Xenograft Model Antitumor Assays*

Substances

  • ErbB Receptors
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphatidylinositol 3-Kinases