title: MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor.
abstract: Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt of signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted to the BCL-2 family proteins for survival are now being targeted therapeutically. For example, navitoclax, a BCL-2/BCL-XL/BCL-W inhibitor, is currently in phase I/II clinical trials in numerous malignancies. However, the related family member, MCL-1, limits the efficacy of navitoclax and other chemotherapeutic agents. In the present study, we identify breast cancer cell lines that depend upon MCL-1 for survival and subsequently determine the mechanism of apoptosis mediated by the MCL-1 selective inhibitor A-1210477. We demonstrate that apoptosis resulting from a loss in MCL-1 function requires expression of the proapoptotic protein BAK. However, expression of BCL-XL can limit apoptosis resulting from loss in MCL-1 function through sequestration of free BIM. Finally, we demonstrate substantial synergy between navitoclax and MCL-1 siRNA, the direct MCL-1 inhibitor A-1210477, or the indirect MCL-1 inhibitor flavopiridol, highlighting the therapeutic potential for inhibiting BCL-XL and MCL-1 in breast cancer.
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Paul
authors.initials: P
authors.lastname: Nimmer
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Milan
authors.initials: M
authors.lastname: Bruncko
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Paul
authors.initials: P
authors.lastname: Hessler
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Lisa
authors.initials: L
authors.lastname: Roberts-Rapp
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: William N
authors.initials: WN
authors.lastname: Pappano
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.affiliation: Oncology Development, AbbVie Inc., North Chicago, Illinois.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois. Darren.Phillips@AbbVie.com.
authors.forename: Darren C
authors.initials: DC
authors.lastname: Phillips
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C528561:navitoclax