Preclinical Evaluation of the Simultaneous Inhibition of MCL-1 and BCL-2 with the Combination of S63845 and Venetoclax in Multiple Myeloma

Merino D, Whittle J, Vaillant F, Serrano A, Gong J, Giner G . Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer. Sci Transl Med. 2017; 9(401). DOI: 10.1126/scitranslmed.aam7049. View

Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno A, Le Toumelin-Braizat G . The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016; 538(7626):477-482. DOI: 10.1038/nature19830. View

Souers A, Leverson J, Boghaert E, Ackler S, Catron N, Chen J . ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013; 19(2):202-8. DOI: 10.1038/nm.3048. View

Kumar S, Kaufman J, Gasparetto C, Mikhael J, Vij R, Pegourie B . Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017; 130(22):2401-2409. DOI: 10.1182/blood-2017-06-788786. View

Witzig T, Timm M, Larson D, Therneau T, Greipp P . Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders. Br J Haematol. 1999; 104(1):131-7. DOI: 10.1046/j.1365-2141.1999.01136.x. View

Touzeau C, Ryan J, Guerriero J, Moreau P, Chonghaile T, Le Gouill S . BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics. Leukemia. 2015; 30(3):761-4. PMC: 4714955. DOI: 10.1038/leu.2015.184. View

Dousset C, Maiga S, Gomez-Bougie P, Le Coq J, Touzeau C, Moreau P . BH3 profiling as a tool to identify acquired resistance to venetoclax in multiple myeloma. Br J Haematol. 2016; 179(4):684-688. DOI: 10.1111/bjh.14251. View

Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson J, Souers A . The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2013; 28(1):210-2. PMC: 3887407. DOI: 10.1038/leu.2013.216. View

Gong J, Khong T, Segal D, Yao Y, Riffkin C, Garnier J . Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. Blood. 2016; 128(14):1834-1844. DOI: 10.1182/blood-2016-03-704908. View

10.

Punnoose E, Leverson J, Peale F, Boghaert E, Belmont L, Tan N . Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models. Mol Cancer Ther. 2016; 15(5):1132-44. DOI: 10.1158/1535-7163.MCT-15-0730. View

11.

Vogler M, Walter H, Dyer M . Targeting anti-apoptotic BCL2 family proteins in haematological malignancies - from pathogenesis to treatment. Br J Haematol. 2017; 178(3):364-379. DOI: 10.1111/bjh.14684. View

12.

Derenne S, Monia B, Dean N, Taylor J, Rapp M, Harousseau J . Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood. 2002; 100(1):194-9. DOI: 10.1182/blood.v100.1.194. View

13.

Brennan M, Chang C, Tai L, Lessene G, Strasser A, Dewson G . Humanized mice enable accurate preclinical evaluation of MCL-1 inhibitors destined for clinical use. Blood. 2018; 132(15):1573-1583. DOI: 10.1182/blood-2018-06-859405. View

14.

Gomez-Bougie P, Maiga S, Tessoulin B, Bourcier J, Bonnet A, Rodriguez M . BH3-mimetic toolkit guides the respective use of BCL2 and MCL1 BH3-mimetics in myeloma treatment. Blood. 2018; 132(25):2656-2669. DOI: 10.1182/blood-2018-03-836718. View

15.

Morales A, Kurtoglu M, Matulis S, Liu J, Siefker D, Gutman D . Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells. Blood. 2011; 118(5):1329-39. PMC: 3152498. DOI: 10.1182/blood-2011-01-327197. View