Genomic classification of lung cancer: toward a personalized treatment

Abstract

Based on the literature findings, recent studies estimate thatapproximately 50-60% of patients with non small cell lung cancer(NSCLC) harbor at list one activated pathway with the most commonmutations being in the Kirsten ras (KRAS) gene (24%) and theepidermal growth factor receptor (EGFR) gene (13-22%), with translocations involving anaplastic lymphoma kinase (ALK) in another5-6% (1, 2). Other pathways are also explored including HER2Neu,BRAF.* EGFR pathway: This year, 2014, marks the tenth anniversary of thediscovery of somatic mutations of the EGFR gene in NSCLC. Thediscovery of activating mutations in the kinase domain of the EGFR gene has determined a revolution in the diagnosis, classification andmanagement of these tumors. EGFR gene encodes for transmembranetyrosine kinase. Upon binding to its ligands, EGFRforms homodimers or heterodimers with other family members(ERBB2, ERBB3 or ERBB4),which inactivate intrinsic receptor tyrosine kinase activity and trigger a phosphorylation cascade of specific tyrosine residues within their cytoplasmicregulatory domains(3). These phosphorylated tyrosine residues activate several signalingpathways including mitogen-activated protein kinase (MAPK)pathway,phosphatidylinositol 3-kinase (PI3K/AKT pathway) and the signaltransducer and activator of transcription pathways (Figure 1). Themutations of EGFR reach 40% in East Asians and 15% in Caucasians(4). The presence of an EGFR mutation predicts likelihood of responseto TKI therapy, with an observedresponse rate of about 80% amongindividuals whose tumors harbor the mutation and only 10% among those whose tumors do not (5, 6).The most frequent mutations havebeen identified in exons 18, 19, 20 and 21. These mutations or deletions, mainly in exon 19, result in increased malignant cell survival,proliferation, growth, invasion, metastatic spread and tumor angiogenesis (7). These activating mutations are more frequently observed in never smokers female with Asian ethnicity and an adenocarcinoma histologic subtype. These mutations are detected in tissue and lung fluid. Many diagnostic methods have been described including Sanger sequencing, pyro sequencing, and next generation sequencing. The identification of mutations induces the use of target therapies. Gefitinib and erlotinib represent the first generation of small EGFR tyrosine kinase inhibitors that selectively target the intracellular tyrosine kinase domain of EGFR, blocking the downstream signaling of the receptor. Unfortunately, the use of these molecules raises many questions concerning the varying response in patients with lung cancers with sensitive EGFR mutations, the occurrence of resistance after a promising initial response, the most appropriate treatment schedule, the treatment strategies after acquisition of resistance to gefintib/erlotininb, the use of EGFR-TKI in adjuvant setting after surgical resection? Some patients with sensitive mutations don’t respond well to the treatment. This has been reported to an inactivation of PTEN resulting in an activation of the PI3K pathway (8).Other authors reported the amplification of the proto-oncogene MET orthe BCl2-interacting mediator of cell death (BIM) (9). All responders eventually develop resistance, most commonly because of the emergence of a gatekeeper mutation in the kinase domain, such as T790M in EGFR-mutated NSCLC or amplification of mesenchymalepithelial transition factor (c-Met) (10, 11). Based on these data, several ongoing trials are assessing the efficacy of novel small molecule EGFR inhibitors for NSCLC including Afatinib or other EGFR/HER inhibitors.