The Pharmacogenomics Journal (2008) 8, 305–314 & 2008 Nature Publishing Group All rights reserved 1470-269X/08 $30.00 www.nature.com/tpj REVIEW Somatic pharmacogenomics in cancer ON Ikediobi Many of the initial examples of the clinical utility of pharmacogenetics were elucidated in the field of oncology. Those examples were largely based on Department of Clinical Pharmacy, School of the existence of germline genetic variation that influences the metabolism of Pharmacy, University of California, San Francisco, cytotoxic drugs. However, with the development of kinase inhibitors, drugs CA, USA designed to preferentially target altered proteins driving oncogenesis, pharmacogenetics in cancer has shifted to understanding the somatic Correspondence: Dr ON Ikediobi, Department of Clinical differences that determine response to these targeted agents. It is becoming Pharmacy, School of Pharmacy, University of increasingly clear that understanding the molecular genetics of cancer will California, 3333 California Street, Box 0613, lead to the further development of targeted therapeutics. Therefore, it is San Francisco, CA 94118, USA. imperative that pharmacogenomics researchers understand the motivations E-mail: [email protected] and challenges of developing targeted therapies to treat cancer as a paradigm for personalized medicine. However, much of the discussion in the pharmacogenomics community in cancer is still largely focused on the germline variants as predictors of drug toxicity. In light of that fact, this review presents a detailed discussion of the development of commonly used targeted therapies for the treatment of hematological and solid tumors, the somatic mutations that determine response to those therapies, and the mechanisms of drug resistance. The Pharmacogenomics Journal (2008) 8, 305–314; doi:10.1038/tpj.2008.8; published online 5 August 2008 Keywords: somatic; mutation; cancer; pharmacogenomics; kinase; inhibitor Introduction Pharmacogenomics is the study of the genetics of interindividual response to drugs and aims at molecular subsetting of patients for more effective therapy.1 The field of pharmacogenomics is especially important in oncology where most clinically used drugs have a narrow therapeutic window, that is the difference between the dose required to achieve the desired therapeutic effect and that causing toxicity, is small.2 Therefore, knowledge of genetic variations, inherited or acquired, that may predict differential response to cancer chemotherapy is key to personalized therapy. Genetic variations in drug effect are classified into two groups: those due to either pharmacokinetic or pharmacodynamic factors. The pharmacokinetic factors that influence drug effect involve the drug’s absorption, distribution, metabolism and excretion.3 In contrast, the pharmacodynamic factors that influence drug effect involve the transport of the drug into the cell and the interaction of the drug (ligand) and its target(s).3 Many of the initial examples from pharmacogenomics in cancer chemo- therapy center on understanding the inherited (germline) interindividual differences involved in drug metabolism (Table 1).2,4–7 However, there are also examples where acquired (somatic) mutations within the tumor DNA are Received 6 March 2008; revised 17 June 2008; accepted 3 July 2008; published online predictive of response to cancer chemotherapy. The elucidation of the signal- 5 August 2008 transduction networks that drive neoplastic transformation has led to rationally Somatic pharmacogenomics ON Ikediobi 306 Table 1 Standard chemotherapeutics and germline variants reported to modulate their action Drug Tumor type Allelic polymorphism Drug action (references) 6-Mercaptopurine ALL TPMT*3A Enhanced toxicity 2,4 Irinotecan Colorectal UGT1A1*28 Enhanced toxicity 5 Tamoxifen Breast CYP2D6*4, *10 Decreased efficacy 6 5-Fluorouracil Colorectal DPYD*2A Enhanced toxicity 7 Abbreviations: ALL, acute lymphoblastic leukemia; CYP2D6, cytochrome P450 2D6; DPYD, dihydropyrimidine dehydrogenase; TPMT, thiopurine methyltransferase; UGT1A1, uridine 50-diphosphate-glucuronosyl-transferase. Numbers in brackets indicate cited references. Table 2 Kinase inhibitors and somatic mutations reported to modulate their drug action Kinase inhibitor Tumor type Gene product Somatic alterations Imatinib CML, ALL, GIST BCR-ABL, KIT, PDGFRA Mutation, deletion, translocation Nilotinib CML BCR-ABL Mutation Dasatinib CML, ALL BCR-ABL Mutation Sunitinib GIST KIT, PDGFRA, FLT3, VEGFR2 Mutation Trastuzumab Breast ERBB2 Amplification, overexpression Pertuzumab Breast ERBB2, EGFR, ERBB3 PTEN deletion, Akt overexpression Lapatinib Breast ERBB2, EGFR ERBB2 amplification Gefitinib NSCLC EGFR Mutation, amplification Erlotinib NSCLC EGFR Mutation, amplification Abbreviations: Akt, serine/threonine protein kinase Akt; ALL, acute lymphoblastic leukemia; BCR-ABL, breakpoint cluster region-ABL; CML, chronic myeloid leukemia; ERBB2, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma-derived oncogene homolog (avian); ERBB3, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3; FLT3, fms-related tyrosine kinase 3; GIST, gastrointestinal stromal tumor; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue; NSCLC, non-small cell lung cancer; PDGFRA, platelet-derived growth factor receptor, a-polypeptide; PTEN, phosphatase and tensin homolog; VEGFR2, vascular endothelial growth factor receptor 2. designed cancer therapeutics that target specific molecular within the tumor DNA but absent within the germline. In abnormalities.8 These targeted therapeutics, unlike tradi- this review, I have highlighted the most common examples tional cytotoxic cancer chemotherapeutics, do not have whereby somatic mutations within tumor DNA determine narrow therapeutic indices and therefore have less severe clinical response to kinase inhibitors (Table 2). side effects. The less severe side effects experienced by taking targeted therapies is as a result of their greater affinity for inhibiting the activity of somatic alterations of the target BCR-ABL, KIT, PDGFR kinase inhibitors kinase(s) that are present within the tumor DNA but absent within the germline. In addition, targeted therapeutics, The first example of the success of small-molecule targeted unlike traditional cytotoxic chemotherapy are available in therapies in treatment of cancer is demonstrated with oral dosage forms for better ease of administration. imatinib, the first small-molecule kinase inhibitor approved Many of the currently known targeted therapeutic agents for clinical use that targets the breakpoint cluster region are protein kinase inhibitors. Kinases are key components of (BCR)-ABL protein tyrosine kinase for the treatment of cell signaling pathways involved in neoplastic transforma- chronic myeloid leukemia (CML). The BCR-ABL protein tion. Genes that encode protein kinases are often over- results from the fusion of the BCR and nonreceptor protein expressed or activated as a result of mutations or tyrosine kinase ABL resulting from a reciprocal chromoso- chromosomal rearrangements in human tumors. Kinase mal translocation t(9;22) producing a shortened chromo- inhibitors are designed as adenosine triphosphate (ATP) some 22, called the Philadelphia (Ph) chromosome. The mimetics and therefore compete with ATP for binding at the resultant fusion protein has constitutive tyrosine kinase active site.8 When bound to the active site of the putative activity enabling the activation of several signaling path- kinase(s), kinase inhibitors reduce the activity of the ways such as Ras, PI3K-Akt and Jak-STAT leading to cell activated protein kinase(s), reducing the cellular oncogenic proliferation and survival.9 The BCR-ABL protein is asso- drive and inducing tumor regression. Interestingly, only a ciated predominantly not only with CML but also with subset of patients respond to these targeted therapies and acute lymphoblastic leukemia.9 Imatinib works by binding their response is governed by the presence of specific to and stabilizing an inactive conformation of the BCR-ABL somatic alterations of the target kinase that are present protein kinase.10,11 Because imatinib also has specificity for The Pharmacogenomics Journal Somatic pharmacogenomics ON Ikediobi 307 the platelet-derived growth factor receptor, a-polypeptide malignancies harboring mutant forms of those proteins.24 (PDGFRA) and KIT protein kinases, it is also used in Another second generation ABL kinase inhibitor that treatment of malignancies associated with dysregulated demonstrates activity against imatinib resistance is dasati- forms of those proteins.11 nib. Dasatinib, although not specifically designed to target Although the initial response to imatinib is dramatic, imatinib-resistant forms of BCR-ABL, is a potent inhibitor of treatment failure quickly ensues. As is the case with the BCR-ABL, Src-family kinases, KIT and PDGFR.25,26 In con- treatment of CML patients with imatinib, patients initially trast to imatinib and nilotinib, dasatinib binds to the active experience complete cytogenetic and hematological remis- conformation of the ABL kinase.27 On the basis of promising sion. However because imatinib fails to deplete leukemic data from phase I and II trials of dasatinib, in patients with stem cells that harbor the BCR-ABL fusion protein,12 some imatinib-resistant CML and Ph-positive ALL patients, it was patients develop resistance to imatinib, particularly in the recently approved in the United States and Europe