Abstract 6812: The third-generation FLT-3 inhibitor, PLM-102, is a promising therapeutic option for venetoclax-resistant AML

Abstract Venetoclax, a selective inhibitor of the anti-apoptotic protein Bcl-2, has been used as a first-line treatment for acute myeloid leukemia (AML). However, the long-term administration of the drug generally leads to the development of resistance, thereby limiting its therapeutic efficacy. This study aims to evaluate whether PLM-102, an orally available selective and potent FLT3 inhibitor, can overcome venetoclax resistance (VR) in a drug-resistant AML model. To prepare venetoclax-resistant AML cells, the FLT3-ITD-positive MOLM-14 cell line was exposed to increasing concentrations of venetoclax, starting from 10 nM to 1 μM over a period sufficient to induce appreciable resistance. The venetoclax-resistant (VR) cells showed increased phosphorylation of FLT3, AKT, and STAT3 compared to the parental cells. Treatment of the VR cells with PLM-102 ameliorated all activated signaling pathways, restoring them to basal levels more effectively than either tuspetinib or gilteritinib. Additionally, venetoclax, an inhibitor of the anti-apoptotic protein Bcl-2, is known to upregulate MCL-1 as a bypass mechanism. Treatment with PLM-102 reduced MCL-1 and Bcl-2 expression levels and concurrently led to a significant increase in cleaved caspase-3, indicating that PLM-102 induces apoptosis in VR cell lines. In-vivo anti-cancer activities of venetoclax, various FLT3 inhibitors and PLM-102 were compared in the MOLM-14 VR xenograft mouse model. In contrast to the in-vivo study with the parental MOLM-14 model, venetoclax did not show anti-cancer activity in the MOLM-14 VR model, confirming the resistance of VR AML cells in vivo. Notably, PLM-102 demonstrated the highest tumor growth inhibitory (TGI) efficacy compared with those of other FLT3 inhibitors including tuspetinib, gilteritinib and PHI-101. In conclusion, PLM-102 completely inhibited FLT3 kinase and its downstream signaling including AKT and STAT3, inducing apoptosis in VR AML cells along with significant inhibition of the tumor growth in the VR xenograft mouse model. These findings suggest that PLM-102, a third-generation FLT-3 inhibitor, is a promising candidate for overcoming venetoclax resistance and could serve as a therapeutic option for venetoclax-resistant AML. Citation Format: Yun Sun Lee, Min Ji Park, Bongki Ko, Soo Jin Kim, Miran Moon, Soo Yeon Jang, Yong-Chul Kim. The third-generation FLT-3 inhibitor, PLM-102, is a promising therapeutic option for venetoclax-resistant AML [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 6812.