title: A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition.
abstract: BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants, causing late, acquired resistance. We show here that BRAFi (or BRAFi + MEKi) therapy in patients frequently led to rebound phosphorylated AKT (p-AKT) levels in their melanomas early on-treatment. In cell lines, BRAFi treatment led to rebound levels of receptor tyrosine kinases (RTK; including PDGFRβ), phosphatidyl (3,4,5)-triphosphate (PIP3), pleckstrin homology domain recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K-AKT signaling, which could be rescued by the introduction of a mutant AKT1 (Q79K) known to confer acquired BRAFi resistance. Functionally, AKT1(Q79K) conferred BRAFi resistance via amplification of BRAFi-elicited PI3K-AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy.
authors.affiliation: 1The Division of Dermatology, Department of Medicine, 2Division of Surgical Oncology, Department of Surgery, 3Division of Hematology and Oncology, Department of Medicine, 4Jonsson Comprehensive Cancer Center, 5Department of Molecular and Medical Pharmacology, 6David Geffen School of Medicine, University of California, Los Angeles, California; 7Melanoma Institute of Australia, 8Royal Prince Alfred Hospital, 9Westmead Millennium Institute, and 10Westmead Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Hubing
authors.initials: H
authors.lastname: Shi
authors.forename: Aayoung
authors.initials: A
authors.lastname: Hong
authors.forename: Xiangju
authors.initials: X
authors.lastname: Kong
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.forename: Chunying
authors.initials: C
authors.lastname: Song
authors.forename: Gatien
authors.initials: G
authors.lastname: Moriceau
authors.forename: Willy
authors.initials: W
authors.lastname: Hugo
authors.forename: Clarissa C
authors.initials: CC
authors.lastname: Yu
authors.forename: Charles
authors.initials: C
authors.lastname: Ng
authors.forename: Thinle
authors.initials: T
authors.lastname: Chodon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta; C494918:AKT1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt