Abstract B029: Novel FOXM1 degrader STL001 sensitizes diverse group of human cancers to a broad-spectrum of cancer therapies

Abstract Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy resistance and less good patient survival. In AML with NPM1 mutations, NPM1-FOXM1 complex sequesters FOXM1 in the cytoplasm and confers favorable treatment outcomes for AML patients because of FOXM1 inactivation, confirming FOXM1 as a crucial target to overcome drug resistance in AML. Inhibition of FOXM1 in AML sensitizes AML cells to the BCL2 inhibitor, venetoclax. We investigated the FOXM1-BCL2A1 axis and determined that FOXM1 specifically inhibits venetoclax-induced apoptosis in AML via upregulation of BCL2A1. The knockdown of BCL2A1 in AML in the presence of high levels of FOXM1 led to sensitization of AML cells to venetoclax, suggesting that BCL2A1 is a major target of FOXM1 responsible for resistance to venetoclax. Venetoclax in combination with FOXM1 inhibitor STL001 inhibited BCL2A1 and circumvented venetoclax resistance. STL001 is a FOXM1 degrader that re-localizes FOXM1 to cytoplasm followed by degradation by autophagy. Pharmacological inhibition of FOXM1 by STL001 represents a therapeutic strategy to sensitize AML cells to venetoclax-induced apoptosis. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug resistance, making the therapy less effective. Pharmacological inhibition of FOXM1 could be a promising approach to sensitize therapy-resistant cancers to treatment. Here, we explore a novel FOXM1 inhibitor STL001, a first-generation modification drug of our previously reported FOXM1 inhibitor STL427944. STL001 is up to 50 times more efficient than STL427944 in reducing FOXM1 activity in a variety of solid cancer cell lines. Interestingly, STL001 increased the sensitivity of cancer cells to conventional cancer therapies by suppressing both the high-endogenous and drug-induced FOXM1. Notably, STL001 does not provide further sensitization to FOXM1-KD cancer cells, suggesting that the sensitization effect is conveyed specifically through FOXM1 suppression. RNA-seq and gene set enrichment studies revealed prominent suppression of FOXM1-dependent pathways and gene ontologies. Also, gene regulation by STL001 showed extensive overlap with FOXM1-KD, suggesting a high selectivity of STL001 toward the FOXM1 regulatory network. Collectively, STL001 offers intriguing translational opportunities as combination therapies targeting FOXM1 activity in a variety of human cancers. Citation Format: Andrei Gartel, Sanjeev Raghuwanshi. Novel FOXM1 degrader STL001 sensitizes diverse group of human cancers to a broad-spectrum of cancer therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B029.