KRAS - the protooncogene
KRAS gene is Kirsten ras oncogene homolog of mammalian ras gene family and encodes K-Ras protein which regulates cell division and proliferation. Cytogenetically this gene is located in the short arm of chromosome 12 (12p12.1), encoded by 189 amino acids [1]. KRAS protein (also called p21) is a member of RAS/MAPK signalling pathway (for cellular signal transduction) and acts as molecular switch which is turned on by GTP (for cell growth and differentiation) and turned off by GDP molecules. KRAS gene is activated by guanine nucleotide exchange factor (GEF) and inactivated by GTPase activating proteins (GAP) [2]. KRAS is the most frequently mutated oncogene and somatic mutation in this gene results in various types of cancer such as lung, colon and pancreatic.
Around 15 - 25% lung adenocarcinoma/non small cell lung cancer (NSCLC) is related with KRAS mutation (missense mutation that introduces an amino acid substitution most frequently at codons 12, 13 and less frequently codon 61) which affects the KRAS signalling pathways (MAP kinase pathway, AKT/MTOR pathway etc.). The unregulated signalling of RAS through these pathways results in increased cell proliferation, decreased apoptosis, disrupted cellular metabolism and increased angiogenesis that leads to tumor cell proliferation [3]. Currently there is no targeted therapy for the NSCLC patients with KRAS mutation except some promising drug agents such as mitogen activated enzyme kinase inhibitors/MEKi (Trametinib and Selumetinib in combination with chemotherapy), CDK/Cyclin dependent kinase inhibitors (Palbociclib, Abemaciclib) in clinical trial.
Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer which develops via acinar-ductal metaplasia and pancreatic intraepithelial neoplasia (PIN/PanIN), IPMN (intraductal papillary mucinous neoplasia) and AFLs (atypical flat lesions). 90% of PDAC is driven by mutationally (point mutation at codon G12) active KRAS oncogene/oncogenic KRAS signalling which results in intrinsic GTPase activity that block the KRAS and GAP interaction. Oncogenic KRAS signalling involves Raf/Mek/Erk pathway and P13K/Pdk1/Akt pathway and signalling in pancreas generates a fibro-inflammatory microenvironment which promotes neoplastic progression by paracrine stimulation. Also oncogenic KRAS drives metabolic reprogramming in tumor cells by aerobic glycolysis (by increasing glycolytic enzyme expression). Until now there is no cure for PDAC and average life expectancy is less than 5 years.
Around 30% to 50% colorectal cancer (CRC) is associated with KRAS mutation/point substitution (the most frequent is glycine for aspartate) mutation in codon 12, 13, 61, 146 and 154. KRAS gene is an important member of EGFR signalling cascade and involved in intracellular signal transduction [4]. EGFR is a transmembrane receptor tyrosine kinase that is overexpressed in 25% to 75% colorectal tumor/cancer. CRC carcinogenesis involves 3 pathways including chromosomal instability pathway/CIN (defects in chromosomal segregation and telomere stability), microsatellite (short tandem repeats/STRs) instability pathway/MSI (loss of DNA mismatch repair which is most common in CRC) and serrated pathway (progression of serrated polyps)/CpG island methylator phenotype pathway [5]. CIN pathway (also known as adenoma-carcinoma sequence) is the most common one (70%) which involves activation of KRAS proto-oncogene and inactivation of tumor suppressor genes such as APC (that normally blocks transition from G1 to S phase in cell cycle), p53 (that is involved in cell cycle control). CIN also results in aneuploid karyotype, loss of heterozygosity at tumor suppressor gene loci and chromosomal rearrangements [6]. Cetuximab and panitumumab are anti EGFR monoclonal antibodies which are engineered to block the EGFR signalling pathway at the extracellular domain of EGFR receptor. These are currently FDA approved CRC drugs but KRAS mutated patients showed no response to these drugs.
