Abstract 5603: A precision polypharmacology approach to co-target EGFR and PI3 kinase: the power of structure-based drug design to generate therapeutic agents with versatility in multiple combination settings

Abstract Adaptive resistance mechanisms significantly curtail the long term effectiveness of molecular targeted agents directed against a single protein. MTX-531 was computationally designed to selectively target two critical oncogenic drivers, EGFR and PI3 kinase. We recently reported unique structural and pharmacological features of this lead molecule, including strong monotherapy activity against squamous head and neck cancers (HNSCC), which are prone to adaptive resistance when either oncogenic protein is targeted alone (Whitehead et al, Nature Cancer 2024). Based on the central role of the PI3K pathway in driving resistance to a broad spectrum of targeted agents and modalities, we report here pilot studies carried out with MTX-531 to elucidate its potential in combination with other targeted agents, radiation, and immunotherapy. In vivo studies were carried out in KRAS G12D mutant tumor-bearing mice showing that treatment with MTX-531 led to striking enhancement of KRAS inhibitor (MRTX-1133) activity against a broad spectrum of gastrointestinal cancers (pancreatic, colorectal, gastric) as evidenced by a high incidence of durable tumor regressions. In a separate line of investigation, nanomolar potency of MTX-531 against DNA-PK, a PI3K-like family member involved in DNA damage repair, led us to explore the radiosensitizing potential of this molecule in models of HNSCC and triple negative breast cancer. Combination of MTX-531 and daily low dose (2Gy) radiation resulted in prolongation of survival with a high incidence of durable complete regressions in HNSCC. Furthermore, based on the pan-PI3K inhibitory profile of MTX-531, we hypothesized that this molecule would exert immunomodulatory effects to improve therapeutic outcome in the immunotherapy setting. Studies carried out in syngeneic mouse models of pancreatic cancer (KPC) and HNSCC (MOC1) showed that the combination of MTX-531 with anti-PD-1 antibody led to improved survival and increased incidence of objective responses compared to the single agent arms. Collectively, these studies demonstrate the versatility of MTX-531 to serve as the backbone of combination regimens across diverse modalities encompassing treatment with targeted therapies, radiation, or immune checkpoint inhibitors. Based on its promising preclinical profile, MTX-531 represents a first-in-class approach to precision polypharmacology that demonstrates the power of rational structure-based drug design to target multiple resistance drivers in a single molecule. Citation Format: Elizabeth K. Ziemke, Christy L. Frankowski-McGregor, Madeline Walker, Christopher E. Whitehead, Judith S. Sebolt-Leopold. A precision polypharmacology approach to co-target EGFR and PI3 kinase: the power of structure-based drug design to generate therapeutic agents with versatility in multiple combination settings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5603.