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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 11||A-1155463 inhibits BCL-XL, resulting in apoptosis in BCL-XL dependent tumor cells (PMID: 25787766, PMID: 32708132).|
|A-1331852||BCL-XL inhibitor 11||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 11 BCL2 inhibitor 18||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|
|Unknown unknown||breast cancer||not applicable||A-1331852 + Docetaxel||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of A-1331852 and Taxotere (docetaxel) inhibited tumor growth in a metastatic breast cancer cell line xenograft model, with increased efficacy over either agent alone (PMID: 25787766).||25787766|
|Unknown unknown||lung non-small cell carcinoma||not applicable||A-1331852 + Docetaxel||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of A-1331852 and Taxotere (docetaxel) inhibited tumor growth in non-small cell lung cancer cell line xenograft models, with increased efficacy over either agent alone (PMID: 25787766).||25787766|
|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|
|Unknown unknown||Advanced Solid Tumor||not applicable||A-1331852 + Docetaxel||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the addition of A-1331852 enhanced tumor growth inhibition by Taxotere (docetaxel) in several solid tumor cell line xenograft models, and the combination therapy demonstrated increased efficacy over either agent alone in 5/7 of the tested models (PMID: 25787766).||25787766|
|Unknown unknown||Advanced Solid Tumor||not applicable||A-1331852||Preclinical - Cell line xenograft||Actionable||In a preclinical study, A-1331852 inhibited tumor growth in several solid tumor cell line xenograft models (PMID: 25787766).||25787766|