title: Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies.
abstract: OBJECTIVE
  To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models.
  
  
  METHODS
  We established 12 PDXs from BRAF inhibitor-progressed melanoma patients. Following expansion, PDXs were analyzed using targeted sequencing and reverse-phase protein arrays. By using multi-arm preclinical trial designs, we identified efficacious precision medicine approaches.
  
  
  RESULTS
  We identified alterations previously described as drivers of resistance: NRAS mutations in 3 PDXs, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7. At the protein level, re-activation of phospho-MAPK predominated, with parallel activation of PI3K in a subset. Second-line efficacy of the pan-PI3K inhibitor BKM120 with either BRAF (encorafenib)/MEK (binimetinib) inhibitor combination or the ERK inhibitor VX-11e was confirmed in vivo Amplification of MET was observed in 3 PDX models, a higher frequency than expected and a possible novel mechanism of resistance. Importantly, MET amplification alone did not predict sensitivity to the MET inhibitor capmatinib. In contrast, capmatinib as single agent resulted in significant but transient tumor regression in a PDX with resistance to BRAF/MEK combination therapy and high pMET. The triple combination capmatinib/encorafenib/binimetinib resulted in complete and sustained tumor regression in all animals.
  
  
  CONCLUSIONS
  Genomic and proteomic data integration identifies dual-core pathway inhibition as well as MET as combinatorial targets. These studies provide evidence for biomarker development to appropriately select personalized therapies of patients and avoid treatment failures. See related commentary by Hartsough and Aplin, p. 1550.
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania. ckrepler@Wistar.org.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Katrin
authors.initials: K
authors.lastname: Sproesser
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Brafford
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Batool
authors.initials: B
authors.lastname: Shannan
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Marilda
authors.initials: M
authors.lastname: Beqiri
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Bradley
authors.initials: B
authors.lastname: Garman
authors.affiliation: University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Giorgos C
authors.initials: GC
authors.lastname: Karakousis
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Tamer A
authors.initials: TA
authors.lastname: Ahmed
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Poulikos I
authors.initials: PI
authors.lastname: Poulikakos
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, Massachusetts.
authors.forename: Giordano
authors.initials: G
authors.lastname: Caponigro
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, Massachusetts.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, Massachusetts.
authors.forename: Malte
authors.initials: M
authors.lastname: Peters
authors.affiliation: University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
authors.affiliation: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016000:Cluster Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D040901:Proteomics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases