title: Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120.
abstract: We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490-deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer-dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive.
  
  
  CONCLUSIONS
  This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer.
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Shih-Hsun
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Youyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Van Horn
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Tinggui
authors.initials: T
authors.lastname: Yin
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Sean
authors.initials: S
authors.lastname: Buchanan
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Vipin
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Igor
authors.initials: I
authors.lastname: Mochalkin
authors.affiliation: Tailored Therapeutics, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Swee Seong
authors.initials: SS
authors.lastname: Wong
authors.affiliation: Tailored Therapeutics, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Yong Gang
authors.initials: YG
authors.lastname: Yue
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Lysiane
authors.initials: L
authors.lastname: Huber
authors.affiliation: Oncology Business Unit, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Conti
authors.affiliation: Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: James R
authors.initials: JR
authors.lastname: Henry
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: James J
authors.initials: JJ
authors.lastname: Starling
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Plowman
authors.affiliation: Oncology Research, Eli Lilly and Company, Indianapolis, Indiana. peng_sheng-bin@lilly.com.
authors.forename: Sheng-Bin
authors.initials: SB
authors.lastname: Peng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D000066630:Ectopic Gene Expression; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008958:Models, Molecular; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000600963:LY3009120; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D048493:Proto-Oncogene Proteins B-raf