title: Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma.
abstract: The discovery of activating BRAF mutations in approximately 50% of melanomas has led to the development of MAPK pathway inhibitors, which have transformed melanoma therapy. However, not all BRAF-V600E melanomas respond to MAPK inhibition. Therefore, it is important to understand why tumors with the same oncogenic driver have variable responses to MAPK inhibitors. Here, we show that concurrent loss of PTEN and activation of the Notch pathway is associated with poor response to the ERK inhibitor SCH772984, and that co-inhibition of Notch and ERK decreased viability in BRAF-V600E melanomas. Additionally, patients with low PTEN and Notch activation had significantly shorter progression free survival when treated with BRAF inhibitors. Our studies provide a rationale to further develop combination strategies with Notch antagonists to maximize the efficacy of MAPK inhibition in melanoma. Our findings should prompt the evaluation of combinations co-targeting MAPK/ERK and Notch as a strategy to improve current therapies and warrant further evaluation of co-occurrence of aberrant PTEN and Notch activation as predictive markers of response to therapy.
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Minu
authors.initials: M
authors.lastname: Samanta
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Adina
authors.initials: A
authors.lastname: Vultur
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Brafford
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Reyes-Uribe
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Halloran
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chen
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: He
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Denitsa
authors.initials: D
authors.lastname: Hristova
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Discovery Oncology Merck Research Laboratories, Boston, MA, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Samatar
authors.affiliation: Melanoma Medical Oncology and Systems Biology University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Division of Medical Genetics and The Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia PA, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Fukunaga-Kalabis
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Villanueva
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D007191:Indazoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D051880:Receptors, Notch; C587178:SCH772984; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; D053829:Amyloid Precursor Protein Secretases
keywords: BRAF; ERK; melanoma; targeted therapy resistance; Notch