1000/1000
Hot
Most Recent
Non-small cell lung cancer (NSCLC) is a complex disease often driven by activating mutations or amplification of the epidermal growth factor receptor (EGFR) gene, which expresses a transmembrane receptor tyrosine kinase. Targeted anti-EGFR treatments include small-molecule tyrosine kinase inhibitors (TKIs), among which gefitinib and erlotinib are the best studied, and their function more often imaged. TKIs block EGFR activation, inducing apoptosis in cancer cells addicted to EGFR signals.
EGFR | EGFR is one of the four members of the human epidermal growth factor (HER) family transmembrane receptors (HER1/EGFR, HER2, HER3, and HER4). The prevalence of EGFR oncogene mutations is 50% among Asian patients with lung adenocarcinoma and 15% among Western patients [7]. Exon 19 deletions or L858R point mutations in exon 21 account for 90% of the activating mutations in the tyrosine kinase domain of EGFR, resulting in constitutive activation of EGFR without growth factor-induced stimulation, thus promoting cell proliferation [5]. |
KRAS | KRAS is the predominantly mutated RAS isoform (85%) and also the most frequent oncogene in NSCLC [8]. KRAS fosters tumour growth via several mechanisms, including by upregulating rate-limiting enzymes involved in amino acid, fatty acid, or nucleotide biosynthesis, and by stimulating scavenging pathways, such as macropinocytosis and autophagy [9][10], which, in turn provide building blocks for the anabolic routes, also maintaining the energy levels and the cell’s redox potential [11]. |
BRAF | BRAF is a proto-oncogene encoding a serine-threonine protein kinase acting downstream of the RAS/RAF/ERK signalling pathway. BRAF carries signals from membrane receptors (such as EGFR) to the nucleus of the cell to regulate DNA transcription [12]. BRAF is an oncogene located on chromosome 7 involved in several cell functions, including growth, proliferation, survival, and differentiation. Immunotherapy is beginning to show promise as an active therapy in BRAF-mutated NSCLC [13]. |
ALK | The ALK gene encodes the ALK tyrosine kinase receptor and is associated with many types of cancers, including NSCLC [14]. There are three types of ALK mutations: rearrangement (ALK-R), amplification (ALK-A), and point mutation. ALK gene rearrangement is a driving mutation underlying the development of NSCLC [15], which appears to be more common in younger patients and never or light smokers diagnosed with adenocarcinoma. ALK can phosphorylate STAT3 and PI3K independently of ERK to antagonise apoptosis and promote cell survival [16]. |
TP53 | The TP53 gene encodes a DNA damage check point p53 protein, which is at the heart of the cellular decision to proliferate or activate programmed cell death. It regulates the transcription of ~500 genes [17], including cell cycle regulatory genes and transcription factors, and DNA repair genes [18]. Over 50% of human cancers carry loss of function mutations in TP53, with the mutant form acting as a dominant-negative inhibitor towards the wild-type moiety. When chromosomal abnormalities or environment stresses become overwhelming, p53 can arrest cell-cycle progression and induce apoptosis. TP53 alterations carry a worse prognosis in NSCLC [19]. |
MYC | A family of three human proto-oncogenes (c-MYC, l-MYC, and n-MYC) code for transcription factors [20]. In normal cells, depending on nucleotide pools’ levels, growth signals, glucose, or oxygenation, elevated MYC expression can cause apoptosis. Transformed cells can, however, adapt to constitutively elevated levels of MYC expression, resist its apoptotic effects, and only respond to MYC pro-proliferative signals either via loss of growth suppression surveillance mechanisms (e.g., TP53 mutation) and/or by gain of pro-survival signals. MYC is a metastasis gene for NSCLC [21]. |