Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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118 Applying Pharmacogenomics in Therapeuticsan EGFR mutation. However, the prevalence of EGFR mutations varies significantlyacross ethnic groups, from 10% in the white population to more than 40% in Asianpopulations (Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). In Asian NSCLCcancer patients who were nonsmokers or only light smokers, this percentage canbe as high as 60%. For NSCLC with adenocarcinoma histology, the frequency forEGFR mutation is about 10–20%, whereas the rate for squamous histology is about1–15%. It is therefore recommended to test EGFR mutations for all nonsquamouslung cancers, regardless of clinical characteristics.The majority of EGFR mutations are located in the tyrosine kinase domain. Thetwo most frequent EGFR-activating mutations, p.L858R point mutation in exon21 and small deletions in exon 19 (Del19), are responsible for about 90% of cases(Ladanyi and Pao 2008). The less common or rare mutations (a varying frequencyof 1–3%) include p.L861Q mutation, a missense mutation at codon 719 (p.G719X,about 3%) resulting in the substitution of the glycine at amino acid position 719by a cysteine, alanine, or serine, and in-frame insertion mutations in exon 20. Forpatients with a known frequent mutation (Del19 and p.L858R), treatment with anEGFR-TKI, such as erlotinib, gefitinib, or afatinib, is a standard first-line therapy,and multiple phase III trials showed that EGFR-TKI treatment has improved objectiveresponse rate (ORR), progression-free survival (PFS), and health-related qualityof life (HRQOL). However, the sensitivity to EGFR-TKI and PFS are globally lowerfor patients with less frequent or rare EGFR mutations.The use of advanced molecular profiling of EGFR mutation status forpatients with NSCLC to direct targeted therapy with the EGFR-TKIs significantlyimproves the treatment of this disease. However, patients undergoing EGFR-TKItreatments will eventually relapse by acquired resistance (progression after initialbenefit). Acquired resistance may arise from different mechanisms, including pharmacological,biological, and evolutionary selection on molecularly diverse tumors.Polymorphisms in the previously discussed drug transporters such as ABCB1(1236T>C, 2677G>T/A, and 3435C>T) and BCRP (ABCG2, 421C>A) may be relevantfor the pharmacokinetics of the EGFR-TKIs. EGFR mutation heterogeneitycould also contribute to the relapse. The emergence of EGFR exon 20 p.T790Mmutation clones seems to be the most frequent mechanism for acquired resistance(Pao et al. 2005). It seems that there is the presence of a minor subclone (about 1%)of p.T790M mutation before treatment of EGFR-TKI is selected. Although patientswith the EGFR exon 20 p.T790M mutation are resistant to EGFR-TKI treatment,the presence of this alteration predicts a favorable prognosis and indolent diseasecourse, compared to the absence of it after TKI failure. Mutation in the genes ofthe downstream signaling cascade of the EGFR pathway is another mechanismfor acquired resistance of EGFR-TKIs. One example is the KRAS gene, which hasbeen implicated in the pathogenesis of several cancers. Mutations in the KRAS generesult in a constitutively activated KRAS protein that continually triggers thesedownstream signals. Although EGFR TKIs can block EGFR activation, they cannotblock the activity of the mutated KRAS protein. Thus, patients with KRAS mutationstend to be resistant to erlotinib and gefitinib. KRAS mutations are more likelyfound in adenocarcinoma patients who are smokers, and white patients, rather thanEast Asians, and are prognostic for poor survival (Riely et al. 2009).
Pharmacogenomics and Laboratory Medicine119Once a patient experiences acquired resistance, there are several treatment optionsto maintain control of the disease, including local radiation to treat isolated areas ofprogression and continuation of the EGFR-TKI, and adding or switching to cytotoxicchemotherapy. In addition, there are successful novel approaches, including thedevelopment of second-generation and third-generation TKIs and the combinationof TKIs with antibodies directly targeting the receptor. Different from the reversiblefirst-generation TKIs, such as erlotinib and gefitinib, the second-generationEGFR-TKIs form covalent, irreversible binding to the target, and exhibit increasedeffectiveness through a prolonged inhibition of EGFR signaling. Preclinical studiesshowed that the second-generation irreversible TKIs effectively killed cells withacquired resistance to the first-generation TKIs. Currently, there are several irreversibleTKIs, including afatinib, dacomitinib, and neratinib, in the clinical developmentfor NSCLC. Another method to treat acquired resistance is the development of novelTKIs that inhibit both EGFR-activating mutations and T790M mutations. For example,the novel TKI rociletinib (CO-1686) has been shown to be active against boththe EGFR T790M mutation and the activating mutations with only limited inhibitionof the wild-type EGFR. Rociletinib is now in ongoing phase I/II trial for NSCLCpatients with acquired resistance to the first-generation TKIs.ALK Rearrangement in NSCLCAnaplastic lymphoma kinase (ALK), also known as ALK tyrosine kinase receptoror cluster of differentiation 246 (CD246), is encoded by the ALK gene locatedat chromosome 2p23. The ALK tyrosine kinase receptor belongs to the insulinreceptor superfamily of receptor tyrosine kinases (RTKs). The deduced amino acidsequences reveal that the ALK protein comprises an extracellular domain, a putativetransmembrane region, and an intracellular kinase domain. It plays an importantrole in the development of the brain and exerts its effects on specific neurons in thenervous system. Alterations of the ALK gene, such as chromosomal rearrangements,mutations, and amplification, are oncogenic and have been found in various tumors,including anaplastic large cell lymphomas (ALCL) (Lamant et al. 1996; Shiotaet al. 1995), neuroblastoma (Iwahara et al. 1997; Lamant et al. 2000), and NSCLC(Inamura et al. 2009; Martelli et al. 2009; Perner et al. 2008; Takeuchi et al. 2009).The most common genetic alterations are chromosomal rearrangements, such asinversion and translocations that create multiple oncogenic fusion genes involvingALK and different partners, including EML-ALK (chromosome 2), RANBP2-ALK(chromosome 2), ALK/TFG (chromosome 3), NPM1-ALK (chromosome 5), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome10), ALK/CLTC (chromosome 17), ALK/TPM4 ( chromosome 19), and ALK/MSN ( chromosome X).About 3–5% of NSCLC (the vast majority of which are adenocarcinoma) havean inversion of chromosome 2 that fuses the ALK gene with the echinodermmicrotubule-associated protein-like 4 (EML4) gene, and results in the EML4-ALK fusion protein (Choi et al. 2008; Inamura et al. 2008; Martelli et al. 2009;Shinmura et al. 2008; Soda et al. 2007). This fusion protein has functions of bothALK tyrosine kinase and the partner protein. The presence of the partner protein
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ApplyingPharmacogenomicsin Therapeu
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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1Concepts inPharmacogenomics andPer
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Concepts in Pharmacogenomics and Pe
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2Principles ofPharmacogeneticBiotec
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8Clinical Applicationsof Pharmacoge
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11 PharmacoeconogenomicsA Good Marr
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Pharmacoeconomics of Pharmacogenomi
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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