title: Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response.
abstract: Small-molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are being tested in clinical trials for a variety of cancers, but patient selection strategies remain limited. This challenge is partly attributed to the heterogeneous responses elicited by BET inhibition (BETi), including cellular differentiation, senescence, and death. In this study, we performed phenotypic and gene-expression analyses of treatment-naive and engineered tolerant cell lines representing human melanoma and leukemia to elucidate the dominant features defining response to BETi. We found that de novo and acquired tolerance to BETi is driven by the robustness of the apoptotic response, and that genetic or pharmacologic manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further reveal that the expression signatures of the apoptotic genes BCL2, BCL2L1, and BAD significantly predict response to BETi. Taken together, our findings highlight the apoptotic program as a determinant of response to BETi, and provide a molecular basis for patient stratification and combination therapy development.
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Conery
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Centore
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Spillane
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Follmer
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Archana
authors.initials: A
authors.lastname: Bommi-Reddy
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Charlie
authors.initials: C
authors.lastname: Hatton
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bryant
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Amzallag
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Mertz
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts. robert.Sims@constellationpharma.com.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sims
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D018922:HL-60 Cells; D019073:HT29 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D054852:Small Molecule Libraries