title: Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212.
abstract: The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors.
authors.affiliation: Cancer Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Junping
authors.initials: J
authors.lastname: Jing
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.forename: Joanna Dawn
authors.initials: JD
authors.lastname: Holbrook
authors.forename: Aidan
authors.initials: A
authors.lastname: Gilmartin
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McNeil
authors.forename: Theresa
authors.initials: T
authors.lastname: Conway
authors.forename: Christopher
authors.initials: C
authors.lastname: Moy
authors.forename: Sylvie
authors.initials: S
authors.lastname: Laquerre
authors.forename: Kurt
authors.initials: K
authors.lastname: Bachman
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
authors.forename: Yan
authors.initials: Y
authors.lastname: Degenhardt
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D059467:Transcriptome; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins