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Abstract
KRAS mutations are found in about 15-30 % of lung adenocarcinomas. Activation of KRAS leads to upregulation of the MAPK pathway and ultimately to uncontrolled proliferation of tumor cells. While the use of kinase inhibitors, e.g. EGFR or BRAF, has recently revolutionized the treatment of malignant tumors, the development of KRAS antagonists has encountered significant difficulties. To date, specific inhibitors of mutant KRAS have been developed only for glycine to cysteine substitution in the 12th codon (KRAS G12C). This mutation, unlike many other types of damage to RAS family genes in lung tumors, is mainly seen in smokers and is therefore associated with a high mutational burden and greater sensitivity to immunotherapy. Clinical trials of the KRAS(G12C) inhibitors sotorasib and adagrasib have been conducted primarily in lung cancer patients who had received chemotherapy or immune checkpoint inhibitors. Despite the relatively high disease control rates, the median time to progression was only a few months. Randomized comparison of sotorasib and docetaxel showed no difference in overall survival. These data differ significantly from the results of successful clinical trials of other mutant protein inhibitors. The search is on for a "universal" drug that can target tumors with all types of mutations in the RAS family genes. Trials of inhibitors of farnesyltransferase (an enzyme involved in the post-translational modification of RAS proteins) were unsuccessful because alternative pathways of this modification process were initiated. Attempts to manipulate RAS targets, particularly MEK kinase, have also failed, although some clinical observations have demonstrated the prospects of adding autophagy inhibitors to such regimens. Despite the limitations mentioned above, RAS status analysis remains an important part of lung cancer screening, as the detection of RAS gene mutations can convincingly exclude the presence of driver events in the EGFR, ALK, ROS1, NTRK1-3, RET, MET, BRAF and HER2 kinases.
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