title: MCL1 and BCL-xL levels in solid tumors are predictive of dinaciclib-induced apoptosis.
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.
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Booher
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Harold
authors.initials: H
authors.lastname: Hatch
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Dolinski
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Thi
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Lauren
authors.initials: L
authors.lastname: Harmonay
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Ali-Samer
authors.initials: AS
authors.lastname: Al-Assaad
authors.affiliation: BioInformatics, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Ayers
authors.affiliation: BioInformatics, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Nebozhyn
authors.affiliation: BioInformatics, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.affiliation: BioInformatics, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Hirsch
authors.affiliation: BioInformatics, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Theresa
authors.initials: T
authors.lastname: Zhang
authors.affiliation: In vivo Pharmacology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Shi
authors.affiliation: In vivo Pharmacology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Merkel
authors.affiliation: In vivo Pharmacology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Minilik H
authors.initials: MH
authors.lastname: Angagaw
authors.affiliation: In vivo Pharmacology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Yaolin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: In vivo Pharmacology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Long
authors.affiliation: Biomarkers, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Xianlu Q
authors.initials: XQ
authors.lastname: Lennon
authors.affiliation: Biomarkers, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Miselis
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pucci
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Monahan
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Junghoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Anna Georgieva
authors.initials: AG
authors.lastname: Kondic
authors.affiliation: Clinical Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Im
authors.affiliation: Clinical Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Mauro
authors.affiliation: Clinical Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Blanchard
authors.affiliation: Clinical Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Gary
authors.initials: G
authors.lastname: Gilliland
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Fawell
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Leigh
authors.initials: L
authors.lastname: Zawel
authors.affiliation: In vivo Pharmacology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Alwin G
authors.initials: AG
authors.lastname: Schuller
authors.affiliation: Discovery Oncology, Merck Research Laboratories, Boston, Massachusetts, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Strack
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007212:Indolizines; D008297:Male; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D004224:Diterpenes; D004852:Epoxy Compounds; D007212:Indolizines; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010616:Phenanthrenes; D011726:Pyridinium Compounds; D012333:RNA, Messenger; D013449:Sulfonamides; D051020:bcl-X Protein; C001899:triptolide; C553669:dinaciclib; C528561:navitoclax