Dual targeting of CDK4/6 and Bcl-2 exhibits a potent antitumor effect on mantle cell lymphoma.
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ABSTRACT:
SUBMITTER: Che Y
PROVIDER: S-EPMC10345850 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
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Dual targeting of CDK4/6 and Bcl-2 exhibits a potent antitumor effect on mantle cell lymphoma.
Che Yuxuan Y Liu Yang Y Li Yijing Y McIntosh Joseph M JM Jordan Alexa A Yan Fangfang F Wang Wei W Nie Lei L Lee Heng-Huan HH Jin Jingling J Yao Yixin Y Zhao Zhongming Z Jiang Vivian Changying VC Wang Michael M
Blood advances 20230701 14
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2019-04-26 | GSE98268 | GEO
Project description:BackgroundPertuzumab is currently used in combination with trastuzumab as the first-line treatment for HER2-positive metastatic breast cancer. However, pertuzumab was originally developed independently from trastuzumab and was later incidentally found to have synergistic efficacy when combined with trastuzumab, it remains to be seen whether a more potent synergistic efficacy partner exists for trastuzumab.MethodsA trastuzumab-based functional assay was used to screen anti-HER2 antibodies harboring trastuzumab-synergistic antitumor activity. The lead candidate 5G9, in combination with trastuzumab, was further characterized for its bioactivities in cell proliferation, cell apoptosis, antigen-antibody endocytosis and HER2-mediated cell signaling pathway blocking. Finally, animal models were used to evaluate the in vivo synergistic antitumor efficacy of 5G9 in combination with trastuzumab.FindingsCompared to pertuzumab, 5G9 demonstrated more potent synergistic cell growth inhibitory activity when combined with trastuzumab (85% vs. 55%, P<0.001). In addition, 5G9 exhibited a higher internalization rate than pertuzumab (20% vs. 9%, P<0.05), and was able to further synergize with trastuzumab to promote antigen-antibody endocytosis. The internalization rate of the combination of 5G9 and trastuzumab was higher than that of pertuzumab and trastuzumab (35% vs. 14%, P<0.001). In vivo animal studies demonstrated that 5G9 in combination with trastuzumab showed more potent synergistic antitumor efficacy than the combination of pertuzumab and trastuzumab.Interpretation5G9, together with trastuzumab, may provide a potential opportunity for more efficacious treatment of HER2-positive cancers.FundingNational Natural Science Foundation of China; State Key Laboratory of Analytical Chemistry for Life Science.
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