## 4 Discussion
The discrepancies between our findings regarding _HRAS_ mRNA expression depending on NSCLC subtype and calculations based on TNMplot data could be explained by differences in group size. [PERSON] et al. report that the _KRAS_ gene was overexpressed in NSCLC compared to normal tissues, while overexpression of KRAS protein correlated with tumor stage, smoking status and lymph node metastasis of NSCLC [31]. In the present study, _KRAS_ and _HRAS_ expression levels were significantly associated with sex. Moreover, higher _KRAS_ expression was noted among men for lung squamous cell carcinoma. The sex-specific clinicopathological features of NSCLC have been described previously [29]. This might suggest that lung cancer in men and women are dissimilar units, probably on the grounds of differences in hormonal factors and genetic alterations. Promising associations have been found between _KRAS_ and _HRAS_ gene expression in NSCLC and various clinical factors. Many studies have examined the possibility of targeting RAS family genes as a goal for therapy. The main aim of the treatment is inhibition of cell proliferation and tumor growth. Many strategies directly aimed at _KRAS_ mutations and indirectly targeting _KRAS_ have been developed, for instance, targeting other _KRAS_ mutations, reducing the expression of _KRAS_, interrupting membrane localization of KRAS protein or inhibiting KRAS-mediated signal transmission. So far, only two small molecule specific inhibitors for KRAS (G12C)--sotorasib and adagrasib--have been approved by the FDA. Sotorasib binds to Cys12 in the inducible S-IIP and thus inactivates the KRAS-mutated protein. Adagrasib is the RAS GTPase family inhibitor indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who previously received at least one prior systemic therapy. Other specific inhibitors for _KRAS_ (G12C) are currently still in the research clinical phase. An interesting approach seems to be reducing _KRAS_ mRNA expression. For example, [PERSON] et al. found that iExosomes (with siRNA or shRNA targeting _KRAS_ G12D) suppressed _KRAS_ G12D mRNA levels and phosphorylated-ERK protein levels in a pancreatic cell line [32; 33; 34]. The current study examined the effects of three compounds with different effects on the RAS signaling pathway, viz. FTS, deltarasin and Kobe0065, on cell viability, _KRAS_ and _HRAS_ mRNA expression in the A549 NSCLC cell line. There have been only a few reports on the anti-cancer activity of FTS, deltarasin and Kobe0065 on NSCLC cells [15; 35; 36; 37]. In the present study, only 2.5 uM dose of deltarasin decreased the expression of _HRAS_. FTS is a strong RAS inhibitor that acts on the active, GTP-bound forms of RAS family proteins. Through competition with the active RAS form, FTS inhibits cell growth dependent on RAS and transforming activities [35]. In the current study, incubation with FTS resulted in decreased cell viability in a dose-dependent manner with IC50 138.3 uM. [PERSON] et al. found FTS to significantly inhibit A549 cells proliferation with a decrease of 50% at 40 umol/L FTS [35]. [PERSON] et al. obtained IC50 40 umol/L for growth inhibition of A549 cell line 72 h after treatment with FTS. In another study, human colon adenoma-carcinoma cell lines SW480 were treated with FTS that contributed to a decrease in cell viability as well as a reduction in KRAS protein expression [16; 38]. Our results are similar to [PERSON] et al., while they observed a 50% reduction in cell growth in human hepatoma cell lines at a dose of 150 uM [39]. Moreover, they found FTS to have an inhibitory effect on whether tumor cell lines harbor mutated RAS genes or not [35]. Likewise, [PERSON] et al. showed that treatment with FTS alone, as well as in combination with valpro acid, reduced proliferation in non-small cell lung, thyroid and colon cancer cell lines by downregulating RAS [40]. In another study, FTS had a tumor suppressive effect in vitro in bladder cancer cells, but high concentrations of this compound were required [19].