Abstract
Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Cyclic N-Oxides / administration & dosage
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Cyclic N-Oxides / pharmacology*
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Drug Synergism
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Female
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Gene Amplification
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Humans
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Indoles / administration & dosage
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Indoles / pharmacology
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Indolizines / administration & dosage
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Indolizines / pharmacology*
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Mice
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Oxazoles / administration & dosage
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Oxazoles / pharmacology
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Protein Kinase Inhibitors / pharmacology*
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Pyridines / administration & dosage
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Pyridines / pharmacology
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Pyridinium Compounds / administration & dosage
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Pyridinium Compounds / pharmacology*
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Quinazolines / administration & dosage
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Quinazolines / pharmacology
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Quinolines / administration & dosage
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Quinolines / pharmacology
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Random Allocation
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology
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Xenograft Model Antitumor Assays
Substances
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A-1210477
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Cyclic N-Oxides
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Indoles
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Indolizines
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Oxazoles
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Protein Kinase Inhibitors
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Pyridines
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Pyridinium Compounds
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Quinazolines
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Quinolines
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Sulfonamides
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tucatinib
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dinaciclib
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ERBB2 protein, human
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Receptor, ErbB-2
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neratinib