Abstract 1134: The LSD1 inhibitor INCB059872 is a possible therapeutic option for venetoclax-resistant AML
Authors: Diamond Melody , Chadderton Antony , He Chunhong , Wu Liangxing , Yao Wenqing , Koblish Holly , Lee Sang Hyun , Stubbs Matthew C. 
Published: July 2021

Abstract
Pharmacological inhibition of lysine specific demethylase 1 (LSD1) has shown preclinical promise as a therapy for patients with acute myeloid leukemia (AML). Numerous studies have shown that LSD1 inhibitors differentiate AML cells, decreasing the number of blast and leukemia stem cells, leading to therapeutic efficacy. With the recent clinical success of the BCL-2 inhibitor venetoclax in AML, the landscape of unmet needs for AML patients has changed. The high response rate of AML patients receiving venetoclax in combination with azacitidine as first line AML therapy means differentiation therapy with LSD1 inhibitors would be more acceptable either in combination with venetoclax, or post-venetoclax treatment. Here we explore the effects of combining the LSD1 inhibitor INCB059872 with venetoclax in AML lines that are sensitive and resistant to venetoclax. First, to test for benefits from combining venetoclax with INCB059872, we performed in vivo studies using several AML models, and each showed that combination of venetoclax and INCB059872 resulted in additive to more-than-additive efficacy when compared to either agent alone. Next, to test the effects of INCB059872 in a post-venetoclax AML setting, we generated MV4;11 and Molm13 venetoclax resistant cells by culturing them in increasing concentrations of venetoclax. These cells had elevated MCL1 expression and decreased sensitivity to venetoclax in cell proliferation assays. Treating venetoclax-resistant cells with INCB059872 alone had very little effect on their growth, while the parental cell lines were sensitive to INCB059872. However, when INCB059872 was combined with venetoclax, growth inhibition in the venetoclax resistant cell lines was apparent. Combination of INCB059872 with venetoclax appears to alter levels of the apoptotic machinery to levels that may be pro-apoptotic. In vivo studies showed no survival effects in mice engrafted with venetoclax resistant cells and treated with either venetoclax or INCB059872, but significant survival benefit was seen with the INCB059872+venetoclax combination. A third venetoclax resistant model was developed by serial transplant of murine MLL-AF9 expressing bone marrow cells from mice dosed for two weeks with 10 mg/kg QD venetoclax. After three serial transplants, resistance to venetoclax arose, while cells transplanted from vehicle treated mice were still venetoclax responsive. Venetoclax resistant MLL-AF9 driven AML was also resistant to INCB059872, but the combination of venetoclax and INCB059872 was able to slow the onset of venetoclax resistant MLL-AF9 driven AML significantly. The data presented here suggest that inhibition of LSD1 with INCB059872 may alter the expression of apoptotic machinery of AML cells leading to combinatorial therapeutic benefit when co-administered with venetoclax, and that INCB059872 combined with venetoclax may overcome acquired venetoclax resistance in AML.
Citation Format: Melody Diamond, Antony Chadderton, Chunhong He, Liangxing Wu, Wenqing Yao, Holly Koblish, Sang Hyun Lee, Matthew C. Stubbs. The LSD1 inhibitor INCB059872 is a possible therapeutic option for venetoclax-resistant AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1134.