title: Dissecting Therapeutic Resistance to ERK Inhibition.
abstract: The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V(600E)) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAF(V600) (E)-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G(186D)) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548-59. ©2016 AACR.
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Sharda
authors.initials: S
authors.lastname: Jha
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Erick J
authors.initials: EJ
authors.lastname: Morris
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Alan
authors.initials: A
authors.lastname: Hruza
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: My Sam
authors.initials: MS
authors.lastname: Mansueto
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Gottfried K
authors.initials: GK
authors.lastname: Schroeder
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Jaren
authors.initials: J
authors.lastname: Arbanas
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Daniel
authors.initials: D
authors.lastname: McMasters
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Restaino
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Priya
authors.initials: P
authors.lastname: Dayananth
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Stuart
authors.initials: S
authors.lastname: Black
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Elsen
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mannarino
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Alan
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fawell
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Leigh
authors.initials: L
authors.lastname: Zawel
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts. ahmed.samatar@therametbio.com ljayaraman@ceruleanrx.com.
authors.forename: Lata
authors.initials: L
authors.lastname: Jayaraman
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, Boston, Massachusetts. ahmed.samatar@therametbio.com ljayaraman@ceruleanrx.com.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Samatar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases