Expression profiling-based subtyping identifies novel non-small cell lung cancer subgroups and implicates putative resistance to pemetrexed therapy

J Thorac Oncol. 2012 Jan;7(1):105-14. doi: 10.1097/JTO.0b013e3182352a45.

Abstract

Introduction: A challenge of cancer therapy is to optimize therapeutical options to individual patients. Cancers with similar histology may show dramatically different responses to therapy, indicating that a refined approach needs to be developed to classify tumors by intrinsic characteristics that may predict response to chemotherapy. Global expression profile-based classification has the potential to identify such tumor-intrinsic subclasses. Pemetrexed effectiveness has been related to the expression of its target thymidylate synthase. The relatively frequent resistance of squamous cell carcinoma to Pemetrexed is correlated with high levels of thymidylate synthase expression.

Methods: A global expression profile-based molecular classification of non-small cell lung cancer (NSCLC) was performed. Gene expression was used to predict Pemetrexed responsiveness. The distinct molecular attributes of NSCLCs predicted likely to be resistant to Pemetrexed were bioinformatically characterized. We tested if routine immunohistochemical markers can be used to distinguish putative Pemetrexed responders, predicted by gene signatures, from nonresponders.

Results: Ninety NSCLCs were divided into six subclasses by gene expression signatures. The relevance of this novel phenotyping was linked to other tumor characteristics. Two of the subclasses correlated to putative Pemetrexed resistance. In addition, the identified signature genes characterizing putative Pemetrexed responsiveness predicted therapeutic benefit in a subset of squamous cell carcinoma.

Conclusions: Gene expression signatures can be used to identify NSCLC subgroups and have potential to predict resistance to Pemetrexed therapy. We suggest that a combination of classical pathological markers can be used to identify molecular tumor subclasses associated with predicted Pemetrexed response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoid Tumor / drug therapy
  • Carcinoid Tumor / genetics
  • Carcinoid Tumor / metabolism
  • Carcinoma, Large Cell / drug therapy
  • Carcinoma, Large Cell / genetics*
  • Carcinoma, Large Cell / metabolism
  • Carcinoma, Neuroendocrine / drug therapy
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Cell Cycle Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / metabolism
  • Folate Receptor 1 / metabolism
  • Gene Expression Profiling
  • Glutamates / therapeutic use*
  • Guanine / analogs & derivatives*
  • Guanine / therapeutic use
  • Humans
  • Keratin-5 / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Microarray Analysis
  • Microtubule-Associated Proteins / metabolism
  • Minichromosome Maintenance Complex Component 6
  • Multidrug Resistance-Associated Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Pemetrexed
  • Protein-Serine-Threonine Kinases / metabolism
  • Reduced Folate Carrier Protein / metabolism
  • Thymidylate Synthase / metabolism
  • Transcription Factors
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • ASCL1 protein, human
  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • CDCA7 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Folate Receptor 1
  • Glutamates
  • KRT5 protein, human
  • Keratin-5
  • Microtubule-Associated Proteins
  • Multidrug Resistance-Associated Proteins
  • Nuclear Proteins
  • Reduced Folate Carrier Protein
  • SLC19A1 protein, human
  • TP53 protein, human
  • TTF1 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Pemetrexed
  • Guanine
  • Thymidylate Synthase
  • MAST4 protein, human
  • ErbB Receptors
  • Protein-Serine-Threonine Kinases
  • MCM6 protein, human
  • Minichromosome Maintenance Complex Component 6
  • multidrug resistance-associated protein 1