Abstract 4024: Combining selumetinib with BH3 mimetics enhances activity in MAPK-activated acute myeloid leukemia
Authors: Andersen Courtney L. , Cheraghchi-Bashi Azadeh , Jaaks Patricia , Coker Elizabeth A. , Burke Kathleen , Cidado Justin , Smith Paul , Reimer Corinne , Tibes Raoul , Garnett Mathew , Mettetal Jerome 
Published: June 2022

Abstract
Mitogen-activated protein kinase (MAPK) pathway alterations comprise some of the most frequent mutations in newly diagnosed acute myeloid leukemia (AML). Moreover, MAPK pathway alterations are also emerging as potential mechanisms of resistance to targeted therapy in AML including FLT3 inhibitors and venetoclax. In an ex vivo pharmacologic analysis of primary AML samples, sensitivity to the MEK inhibitor selumetinib (ARRY-142886) was enriched in patient samples resistant to venetoclax. Clinical activity of MAPK pathway inhibitors such as selumetinib has been explored in AML but monotherapy responses were modest. Another MEK inhibitor, cobimetinib, is currently being tested in combination with venetoclax in AML. We sought to understand whether combining selumetinib with BH3 mimetics such as venetoclax would improve efficacy in AML models. We evaluated combination activity of selumetinib plus venetoclax or the MCL1 inhibitor AZD5991 in a panel of AML cell lines. Cells were exposed to a 6x6 matrix of both agents for 72hrs and then viability assessed using CellTiter-Glo. Combination benefit was assessed using highest single agent (HSA) analysis. Selumetinib+AZD5991 demonstrated strong combination benefit (HSA score &gt;0.1, Emax &gt;0.5) in 4/19 AML cell lines. Selumetinib+venetoclax showed strong combination activity in 6/19 lines. Three lines showed benefit with both combinations. Many of these cell lines harbor MAPK pathway mutations including OCI-AML5 (SOS1N233Y, NF1K1385R), ML-2 (KRASA146T), HL-60 (NRASQ61L), and Nomo-1 (KRASG13D). Selumetinib treatment also led to robust BIM induction in vitro. Nomo-1 xenografts were evaluated for in vivo sensitivity to venetoclax (100 mg/kg qd PO), 5-azacytidine (1mg/kg BID q8h 3days on/4days off IP), AZD5991 (30mpk bid q2h qw IV), selumetinib (10 mg/kg bid q8h PO), as well as combinations of venetoclax+5-aza, AZD5991+selumetinib, and venetoclax+selumetinib. Venetoclax and venetoclax+5-aza treatment were ineffective. Selumetinib monotherapy led to 63% tumor growth inhibition (TGI) but tumors eventually grew out through treatment. The combination of selumetinib+venetoclax slightly improved efficacy (81% TGI) but markedly delayed tumor outgrowth (selumetinib monotherapy arm reached mean tumor volume &gt;1000 mm3 on day 17, selumetinib+venetoclax reached average of ~966 mm3 on day 28). Reducing venetoclax dose (30mg/kg qd) or frequency (100mg/kg 3days on/4days off) maintained most of the combination efficacy. Selumetinb+AZD5991 also strongly improved efficacy compared to either monotherapy (88% TGI, mean tumor volume did not exceed ~400mm3 by day 28). Together these data suggest potential for combining MEK inhibitors with BH3 mimetics in AML. Work is ongoing to further understand how scheduling impacts combination efficacy, evaluate the triple combination of selumetinib+BH3 mimetic+azacytidine, and assess efficacy in disseminated models.
Citation Format: Courtney L. Andersen, Azadeh Cheraghchi-Bashi, Patricia Jaaks, Elizabeth A. Coker, Kathleen Burke, Justin Cidado, Paul Smith, Corinne Reimer, Raoul Tibes, Mathew Garnett, Jerome Mettetal. Combining selumetinib with BH3 mimetics enhances activity in MAPK-activated acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4024.