Reference Detail

Ref Type

Journal Article

PMID

(25787766)

Authors

Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, Belmont LD, Nimmer P, Xiao Y, Ma XM, Lowes KN, Kovar P, Chen J, Jin S, Smith M, Xue J, Zhang H, Oleksijew A, Magoc TJ, Vaidya KS, Albert DH, Tarrant JM, La N, Wang L, Tao ZF, Wendt MD, Sampath D, Rosenberg SH, Tse C, S Huang DC, Fairbrother WJ, Elmore SW, Souers AJ

Title

Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	7	279	2015 Mar 18	279ra40	Sci Transl Med

URL

Abstract Text

The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
A-1155463	A-1155463	1	0
A-1331852	A-1331852	0	0
Navitoclax	Navitoclax	0	2

Drug Name	Synonyms	Drug Classes	Drug Description
A-1155463	A1155463	BCL-XL inhibitor 14	A-1155463 inhibits BCL-XL, resulting in apoptosis in BCL-XL dependent tumor cells (PMID: 25787766, PMID: 32708132).
A-1331852		BCL-XL inhibitor 14	A-1331852 inhibits BCL-XL, resulting in increased tumor cell apoptosis and decreased tumor growth (PMID: 25787766, PMID: 32145345).
Navitoclax	ABT-263	BCL-XL inhibitor 14 BCL2 inhibitor 27	Navitoclax (ABT-263) is a BCL2, BCL-XL, and BCL-W inhibitor, which may enhance the efficacy of chemotherapeutics (PMID: 25787766, PMID: 32513939).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK2 V617F	acute myeloid leukemia	sensitive	A-1155463	Preclinical	Actionable	In a preclinical study, acute myeloid leukemia cells harboring JAK2 V617F demonstrated sensitivity to A-1155463 in culture (PMID: 25787766).	25787766