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|Ref Type||Journal Article|
|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||Science translational medicine|
|Date||2015 Mar 18|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade 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 26||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|