A First-in-Class Selective Inhibitor of Egfr and PI3K Offers a Single-Molecule Approach to Targeting Adaptive Resistance

Authors

Christopher E Whitehead
Elizabeth K Ziemke
Christy L Frankowski-McGregor
Rachel A Mumby
June Chung
Jinju Li
Nathaniel Osher
Oluwadara Coker
Veerabhadran Baladandayuthapani
Scott Kopetz
Judith S Sebolt-Leopold

Publication Date

8-1-2024

Journal

Nature Cancer

DOI

10.1038/s43018-024-00781-6

PMID

38992135

PMCID

PMC11357990

PubMedCentral® Posted Date

7-11-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Animals, ErbB Receptors, Mice, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Cell Line, Tumor, Phosphoinositide-3 Kinase Inhibitors, Colorectal Neoplasms, Female, Phosphatidylinositol 3-Kinases, Head and Neck Neoplasms

Published Open-Access

yes

Recommended Citation

Whitehead, Christopher E; Ziemke, Elizabeth K; Frankowski-McGregor, Christy L; et al., "A First-in-Class Selective Inhibitor of Egfr and PI3K Offers a Single-Molecule Approach to Targeting Adaptive Resistance" (2024). Faculty, Staff and Student Publications. 4636.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4636