ABSTRACT
Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.
Subject(s)
Apoptosis/drug effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplasms/metabolism , Pyridinium Compounds/pharmacology , bcl-X Protein/metabolism , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacology , Apoptosis/genetics , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cyclic N-Oxides , Disease Models, Animal , Diterpenes/pharmacology , Drug Resistance, Neoplasm/genetics , Drug Synergism , Epoxy Compounds/pharmacology , Female , Gene Dosage , Humans , Indolizines , Male , Mice , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Neoplasms/genetics , Phenanthrenes/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sulfonamides/pharmacology , Xenograft Model Antitumor Assays , bcl-X Protein/geneticsABSTRACT
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.
