title: A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors.
abstract: BACKGROUND
  Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence.
  
  
  METHODS
  We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets.
  
  
  RESULTS
  The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer.
  
  
  CONCLUSIONS
  These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.
authors.affiliation: Department of Molecular Profiling and Research Informatics, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.forename: Michael
authors.initials: M
authors.lastname: Nebozhyn
authors.forename: Rich
authors.initials: R
authors.lastname: Klinghoffer
authors.forename: Jason
authors.initials: J
authors.lastname: Frazier
authors.forename: Michael
authors.initials: M
authors.lastname: Chastain
authors.forename: William
authors.initials: W
authors.lastname: Arthur
authors.forename: Brian
authors.initials: B
authors.lastname: Roberts
authors.forename: Theresa
authors.initials: T
authors.lastname: Zhang
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.forename: Brian
authors.initials: B
authors.lastname: Haines
authors.forename: Jannik
authors.initials: J
authors.lastname: Andersen
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nagashima
authors.forename: Cloud
authors.initials: C
authors.lastname: Paweletz
authors.forename: Bethany
authors.initials: B
authors.lastname: Lynch
authors.forename: Igor
authors.initials: I
authors.lastname: Feldman
authors.forename: Hongyue
authors.initials: H
authors.lastname: Dai
authors.forename: Pearl
authors.initials: P
authors.lastname: Huang
authors.forename: James
authors.initials: J
authors.lastname: Watters
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D004791:Enzyme Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering; D018631:ras Proteins; C117307:KRAS protein, human