title: Maximizing the Efficacy of MAPK-Targeted Treatment in PTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition.
abstract: The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAF(MUT)) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTEN(LOF)) occurs in approximately 40% of BRAF(MUT) melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTEN(LOF)/BRAF(MUT) melanoma. Large-scale compound sensitivity profiling revealed that PTEN(LOF) melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R-PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTEN(LOF)/BRAF(MUT) melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTEN(LOF)/BRAF(MUT) melanoma patients to achieve maximal response.
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Herkert
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Kauffmann
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mollé
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ferrat
authors.affiliation: NIBR, Analytical Sciences and Imaging, Basel, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Voshol
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Janina
authors.initials: J
authors.lastname: Juengert
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Hélène
authors.initials: H
authors.lastname: Erasimus
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Grégory
authors.initials: G
authors.lastname: Marszalek
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Malika
authors.initials: M
authors.lastname: Kazic-Legueux
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Billy
authors.affiliation: Novartis Pharma, OTM Translational Research, Cambridge, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Ruddy
authors.affiliation: NIBR, Disease Area Oncology, Cambridge, Massachusetts.
authors.forename: Mark
authors.initials: M
authors.lastname: Stump
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Guthy
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Mitko
authors.initials: M
authors.lastname: Ristov
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Keith
authors.initials: K
authors.lastname: Calkins
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.affiliation: NIBR, Disease Area Oncology, Cambridge, Massachusetts.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Disease Area Oncology, Basel, Switzerland. Saskia.brachmann@novartis.com.
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Brachmann
mesh_terms: D017209:Apoptosis; D016923:Cell Death; D049109:Cell Proliferation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D040901:Proteomics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
chemical_list: D017526:Receptor, IGF Type 1; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human