Developments for Personalized Medicine of Lung Cancer Subtypes: Mass Spectrometry-Based Clinical Proteogenomic Analysis of Oncogenic Mutations.
Molecular therapies targeting lung cancers with mutated epidermal growth factor receptor (EGFR) by EGFR-tyrosin kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, changed the treatment system of lung cancer. It was revealed that drug efficacy differs by race (e.g., Caucasians vs. Asians) due to oncogenic driver mutations specific to each race, exemplified by gefitinib / erlotinib. The molecular target drugs for lung cancer with anaplastic lymphoma kinase (ALK) gene translocation (the fusion gene, EML4-ALK) was approved, and those targeting lung cancers addicted ROS1, RET, and HER2 have been under development. Both identification and quantification of gatekeeper mutations need to be performed using lung cancer tissue specimens obtained from patients to improve the treatment for lung cancer patients: (1) identification and quantitation data of targeted mutated proteins, including investigation of mutation heterogeneity within a tissue; (2) exploratory mass spectrometry (MS)-based clinical proteogenomic analysis of mutated proteins; and also importantly (3) analysis of dynamic protein-protein interaction (PPI) networks of proteins significantly related to a subgroup of patients with lung cancer not only with good efficacy but also with acquired resistance. MS-based proteogenomics is a promising approach to directly capture mutated and fusion proteins expressed in a clinical sample. Technological developments are further expected, which will provide a powerful solution for the stratification of patients and drug discovery (Precision Medicine).
Translational Medicine Informatics, St. Mariana University School of Medicine, Kanagawa, Japan. t-nisimura-tmu@hotmail.co.jp.|Research & Development, Biosys Technologies Inc., Tokyo, Japan. t-nisimura-tmu@hotmail.co.jp.|Center of Excellence in Biological and Medical Mass Spectrometry, BMC, Lund University, Lund, Sweden. t-nisimura-tmu@hotmail.co.jp.
Toshihide
T
Nishimura
Translational Medicine Informatics, St. Mariana University School of Medicine, Kanagawa, Japan.|Chest Surgery, St. Mariana University School of Medicine, Kanagawa, Japan.
Haruhiko
H
Nakamura
D000230:Adenocarcinoma / Q000145:classification / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D044466:Asian People; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D000077156:Gefitinib; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D013058:Mass Spectrometry / Q000379:methods*; D058990:Molecular Targeted Therapy; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057285:Precision Medicine; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044465:White People
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C522504:EML4-ALK fusion protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C099282:RET protein, human; C062333:ROS1 protein, human
Clinical proteogenomics; Drug resistance; Fusion gene; Lung adenocarcinoma; Mass spectrometry (MS); Oncogenic driver mutation; Precision medicine; Protein-protein interaction (PPI) network; Third-generation EGFR tyrosine kinase inhibitor (TKI)