Abstract
Lung cancer has recently become one of the most common and lethal malignancies; the prevalence of non-small cell lung cancer (NSCLC) is also increasing. Most colorectal and pancreatic cancers as well as NSCLCs are caused by RAS oncogene mutations. These mutations are split into three subtypes: the neuroblastoma RAS viral oncogene homolog (NRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and Kirsten rat sarcoma viral oncogene homolog (KRAS). The GTPase activity of RAS proteins is largely affected by these mutations, causing them to remain activated, resulting in uncontrolled cell growth. In this review, three of the most common RAS gene variants-KRAS G12C, KRAS G12V, and KRAS G12D-are described. Together, these variants account for three-quarters of all KRAS mutations. KRAS G12C is found predominantly in smokers and lung adenocarcinoma patients. Nevertheless, a plethora of potent inhibitors such as sotorasib, adagrasib, GDC-6036, JNJ-74699157, and D-1553, are used, with the most effective being sotorasib and adagrasib. Furthermore, unlike other KRAS mutations, KRAS G12C signaling preferentially activates downstream Ral A/B and RAF/MEK/ERK pathways, resulting in lower levels of phosphorylated AKT, a trait shared with KRAS G12V mutations. The KRAS G12V mutation has a significant impact on failure-free survival and overall survival. Finally, when combined with TP53 co-mutations, the KRAS G12D mutation could be a potential immunotherapy biomarker. It is also worth noting that KRAS G12D mutations are associated with a low tumor mutational burden. Owing to the severity and prevalence of NSCLC, a thorough investigation into these findings is warranted, making treatment innovation all the more critical.