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

  • Nat Cancer. 2024 Jul 11. doi: 10.1038/s43018-024-00781-6.
Christopher E Whitehead  #  1  2 ,  Elizabeth K Ziemke  #  1 ,  Christy L Frankowski-McGregor  #  1 ,  Rachel A Mumby  1 ,  June Chung  1 ,  Jinju Li  3 ,  Nathaniel Osher  3 ,  Oluwadara Coker  4 ,  Veerabhadran Baladandayuthapani  3  5 ,  Scott Kopetz  4 ,  Judith S Sebolt-Leopold  6  7  8  9
Affiliations
  • 1. Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
  • 2. MEKanistic Therapeutics, Inc., Ann Arbor, MI, USA.
  • 3. Department of Biostatistics, The University of Michigan School of Public Health, Ann Arbor, MI, USA.
  • 4. The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
  • 6. Department of Radiology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 7. MEKanistic Therapeutics, Inc., Ann Arbor, MI, USA. [email protected].
  • 8. University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. [email protected].
  • 9. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • # Contributed equally.
PMID: 38992135 DOI: 10.1038/s43018-024-00781-6
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.

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