Non-coding RNAs as potential therapeutic targets for receptor tyrosine kinase signaling in solid tumors: current status and future directions

MicroRNAs (miRNAs) are a type of regulatory ncRNAs that primarily function to regulate gene expression by interacting with recognition sites in the 3'-UTR region of mRNA, thereby affecting mRNA stability [23]. The expression of miRNA involves several post-transcriptional cleavage steps. Initially, the transcription of the miRNA locus results in the production of primary miRNA (pri-miRNA). The pri-miRNA then undergoes two cleavage steps, first by the microprocessor enzyme in the nucleus and then by the dicer enzyme in the cytoplasm. The first cleavage step generates pre-miRNA, which is subsequently transported into the cytoplasm by exportin-5 for the final cleavage step, resulting in the formation of mature miRNA. The mature miRNA is a double-stranded polyribonucleotide consisting of a guide strand and a passenger strand. Following the production of the mature form, the miRNA is attached to the argonaute protein (AGO), the passenger strand is removed, and the miRNA-induced silencing complex (miRISC) is formed, consisting of AGO and the guide strand. Any alterations in miRNA expression can impact the expression of target genes and disrupt cellular homeostasis, potentially leading to the development of various diseases, including cancer [24]. These alterations can arise from changes in components of the miRNA processing pathways (e.g., mutations in the dicer gene), genetic variations in miRNA-encoding loci, epigenetic regulation of miRNA expression, and silencing of miRNA expression by long non-coding RNAs (Fig. 2) [25‐28].

Among the various genes that are targeted by miRNAs, RTKs play a crucial role in conjunction with microRNAs, particularly in stress signaling. This association is especially significant in disease-related pathological conditions such as cancer. miRNAs have the ability to function as both oncogenes and tumor suppressors by participating in downstream RTK signaling pathways and regulating the expression of RTK genes [29, 30]. A variety of microRNAs have been associated with the regulation of the signaling pathways downstream of the activated RTKs. For instance, miR-216 modulates the EMT process by modulating the JAK2/STAT3 pathway [31].

The actions and effects of RTKs mentioned above have led to the observation of alterations in their expression in various types of malignancies. One of the key factors contributing to these alterations is the investigation of changes in the levels of miRNAs that target RTKs. This area of research has received significant attention and has been extensively studied.

miR-34a is a microRNA that targets various factors associated with cancer. It regulates cellular processes such as cellular survival, stemness and differentiation, cell cycle, invasion, epithelial-mesenchymal transition (EMT), metabolism, immunity, and epigenetics. RTKs including c-Met, EGFR, AXL, PDGFR-B, and ErbB2 are among the targets of miR-34a [32]. Down-regulation of miR-34a has been reported in several malignancies like breast cancer, colon cancer, gastric cancer, non-small cell lung cancer, and prostate cancer [33‐37]. On the other hand, up-regulation of miR-34a in both tissue and serum levels has been observed in medullary thyroid cancer, making it a potential biomarker for this malignancy [38, 39]. In breast cancer, miR-34a negatively impacts processes like vasculogenic mimicry, migration, and invasion by affecting the AXL receptor tyrosine kinase axis [40]. Overexpression of miR-34a suppresses tumor growth, invasion, and drug resistance in breast cancer [41]. In a meta-analysis conducted in 2017 by Imani et al., the use of miR-34a as a biomarker for breast cancer risk was examined. The analysis indicated a pooled sensitivity of 85.5% (OR 83.8–87% (95% CI)) and specificity of 70% (OR 65.8–74.1% (95% CI)). The overall area under the curve (AUC) was calculated to be 0.8 [42]. These findings indicate that miR-34a shows promise as a potential biomarker for breast cancer. Furthermore, the tumor suppressive effects of miR-34a suggest that it could be utilized as a treatment approach for breast cancer. Several studies have already been conducted on this matter [43‐46]. These studies have explored the possibility of using an appropriate drug delivery system to target and deliver miR-34a specifically to breast cancer cells, thereby enhancing its therapeutic effects. miR-34a is also a regulator of RTKs by affecting MET gene expression and plays a role in gastric cancer proliferation and metastasis [35, 47, 48]. Furthermore, miR-34a regulates downstream signaling pathways such as PI3K/Akt and Wnt/β-catenin [49, 50].

miR-7 is a well-studied regulatory microRNA that has been extensively researched. Its target genes such as EGFR and its downstream effectors, protein kinase B (Akt) and extracellular kinase regulator ½ (ERK ½), are associated with RTK [51]. Studies on breast cancer cell lines have demonstrated that miR-7 plays a role in regulating various cellular processes, including EMT, metastasis, tumor-associated angiogenesis, as well as increased radiosensitivity [52‐54]. In gastric cancer, miR-7 directly inhibits the expression of IGF1R, EGFR, and mTOR, which are the downstream effectors of the PI3K/Akt pathway. This leads to increased sensitivity to cisplatin treatment, apoptosis, as well as negative regulation of metastasis and proliferation in gastric cancer tissues [55‐58]. The under-expression of miR-7 is considered a poor prognostic indicator and therapeutic delivery of this microRNA has been shown to reduce vasculogenesis and inflammation in gastric cancer [59]. miR-7 influences a variety of RTK-associated signaling pathways including EGFR downstream pathways Ras/Raf/MEK/ERK1/2 and PI3K/Akt/mTOR, as well as IGF1R/IRS pathway. It is also implicated in gefitinib-mediated cytotoxicity by affecting the expression of these molecular components [60, 61]. Additionally, miR-7 acts as a mediator in regulating cellular proliferation, migration, and invasion in non-small cell lung cancer (NSCLC) through the ERK/MAPK signaling pathway [62].

In addition to miR-7, other microRNAs such as miR-146a, miR-375, and miR-495, target the EGFR-encoding mRNAs [48, 63, 64]. miR-146a is a regulator of cellular proliferation, apoptosis, and invasion. Its expression is down-regulated in gastric cancer tissue samples compared to controls [65‐68]. The expression levels of miR-146a show a 98% sensitivity in distinguishing affected tissue from normal surroundings. In addition, higher expression of miR-146a indicates a better response to chemotherapy [69]. miR-375 targets ErbB2 and EGFR subtype, along with the receptor d’Origine Natais (RON) RTK, and the downstream signaling effector JAK2. It is involved in regulating cellular proliferation, migration, and invasion in gastric cancer. Higher levels of miR-375 are also an indicator of favorable treatment response [64, 70, 71]. Moreover, lower serum levels of this microRNA serve as a marker of poor prognosis with an AUC of 0.871 and are associated with lymph node metastasis and a higher tumor stage [72]. miR-375 is under-expressed in NSCLC tissue and plasma samples, and is associated with lymph node and brain metastasis, advanced disease stage, and shorter overall survival [73‐75]. Such a pattern of alteration has also been implicated in lung squamous cell carcinoma [76]. miR-495 is also another regulator of cellular apoptosis and migration through modulation of the Akt/mTOR pathway and ErbB2 expression [47, 48]. On the other hand, miR-206 mediates the regulation of c-MET, IGF1R, and MAPK3’s expression in gastric cancer. It induces apoptosis and inhibits resistance to cisplatin, metastasis, and proliferation [77‐79].

miR-145 is a microRNA that targets the PI3K/AKT pathway, which is a downstream signaling pathway of various RTKs. By inhibiting the expression of AKT3, miR-145 can enhance the response to treatment [80] and regulate the proliferation and migration of breast cancer cells [81]. Additionally, miR-145 also regulates the expression levels of IGF-1R, another RTK. Results of both in vitro and in vivo investigations on adenoviral transfection of the miR-145 encoding gene in breast cancer cells have shown promising results in inhibiting tumor growth [82].

On the other hand, there are microRNAs such as miR-21, miR-10b, miR-373, and miR-155 that are oncogenic and contribute to breast cancer progression. miR-10b targets HOXD10, which itself plays a role in cellular migration and angiogenic switch in malignant breast cancer. It is also highly expressed in the tumor vasculature. Upregulation of miR-10b expression is associated with breast cancer, as well as glioblastoma, colorectal cancer, and pancreatic adenocarcinoma [83]. miR-21 is also overexpressed in breast cancer tissues and induces metastasis and migration by targeting a variety of effectors like smad7 and PTEN [84, 85]. Both tissue and serum levels of miR-21 have been extensively investigated as potential biomarkers for breast cancer, showing significant associations with a variety of clinicopathological characteristics including tumor grade, risk of metastasis, and hormonal receptor expression profiles [86]. miR-21 has also been extensively studied in hepatocellular carcinoma (HCC) and lung cancer. In HCC, miR-21 targets the tumor suppressor protein PTEN and its overexpression has been observed in serum samples [87, 88]. A meta-analysis by Qu et al. investigating the use of serum miR-21 as a diagnostic biomarker for HCC reported a pooled sensitivity of 85.2%, specificity of 79.2%, and an AUC of 0.89, suggesting its potential for early disease detection [89]. In lung cancer, miR-21 is considered an oncogenic microRNA and has been found to be overexpressed in NSCLC tissues [90]. A recently conducted meta-analysis has estimated the pooled sensitivity and specificity of miR-21 in lung cancer diagnosis to be 77% and 86%, respectively, with an AUC of 0.87. In addition, this biomarker possesses prognostic values with a hazard ratio (HR) of 1.49 for overall survival [91]. Additionally, miR-155, which also regulates the expression of PTEN, is overexpressed in NSCLC tissues and is a predictor of poor outcome [92, 93]. A meta-analysis on the diagnostic and prognostic value of miR-155 reported a pooled sensitivity of 0.82, specificity of 0.78, AUC of 0.87, and a hazard ratio (HR) of 1.26 for poor overall survival [94].

The miR-155, which targets the SOCS1 gene, has shown heterogeneous results in various studies regarding its role in regulating and promoting breast cancer progression [95, 96]. Some studies have reported conflicting findings. However, higher levels of miR-155 have been detected in the serum of breast cancer patients compared to controls, suggesting its potential as a diagnostic biomarker. The validity of miR-155 as a biomarker was supported by an AUC of 0.89 and its elevated levels were significantly associated with tumor grade, stage, and size [97]. These discrepancies in study outcomes may be attributed to differences in study population and conditions. Therefore, it is crucial to conduct studies with controlled conditions and larger sample sizes to obtain more conclusive results.

miR-155 and miR-99a have also been indicated as potential biomarkers for HCC diagnosis. miR-99a, a tumor suppressor, is downregulated in HCC and targets IGF-1R and mTOR. Both microRNAs show promise as diagnostic and prognostic biomarkers, with AUC of 0.799 and 0.84, respectively, according to the findings of a recently conducted meta-analysis [98, 99]. Additionally, high levels of these microRNAs are significantly associated with poor survival time. Furthermore, miR-99a has been explored as a therapeutic approach in both in vitro and in vivo studies, utilizing nano-particle delivery systems [100].

MicroRNAs play a crucial role in regulating various metastasis-associated cellular processes in colorectal cancer (CRC). Among these processes, the EMT is regulated by miR-612, which targets AKT2, and miR-200b, miR-200c, and miR-141, which target ZEB1 and ZEB2. In metastatic CRC tissues, miR-612 is found to be under-expressed, while the miR-141, miR-200b, and miR-200c show patterns of over-expression compared to control tissues [101, 102]. Additionally, miR-1249, miR-590-5p, miR-206, and miR-126 are involved in regulating angiogenesis and hypoxia response by inhibiting the expression of VEGFA. These microRNAs are relatively under-expressed in metastatic CRC tissues. Furthermore, miR-25-3p and miR-143 targets the RTKs VEGFR2 and IGF1R, respectively, to regulate the aforementioned cellular processes [103‐108]. miR-18a and Let-7c target KRAS mRNA and regulate cellular proliferation and invasion, respectively [109, 110]. Another important regulator, miR-124, targets STAT3 and is found to be downregulated in CRC tissue samples, which is a predictor of poor prognosis. In a study by Wang et al., the hazard ratio of the downregulated levels of miR-124 for overall survival and disease-free survival were estimated at 4.634 (p = 0.002) and 4.533 (p = 0.002), respectively [111].

miR-126 plays a significant role in the progression of lung cancer by targeting various genetic components. The Reduction in STAT3 expression levels results in induction of cellular proliferation and migration, as well as decreased susceptibility to apoptosis, as indicated by the under-expression of caspase 3 in NSCLC [112]. Furthermore, miR-126-mediated inactivation of the VEGFA/VEGFR2/ERK pathway is associated with apoptosis and inhibition of metastatic characteristics in NSCLC [113]. Apart from these processes, EMT and angiogenesis are also modulated by miR-126 via targeting PI3K/AKT/Snail and VEGF/FGF-mediated signaling pathways, respectively [114, 115].

The down-regulation of miR-125a-3p is a key factor in determining poor prognosis in NSCLC and is significantly correlated with tumor size and metastasis. Conversely, higher expression of this marker is associated with higher overall and disease-free survival rates in NSLC patients [116]. Similar to miR-126, miR-125a inhibits cellular proliferation and metastasis in NSCLC by targeting STAT3 [117]. It is also a modulator of the HER2 receptor in small cell lung cancer (SCLC), and its under-expression is associated with the anti-tumor effects of cytotoxic drugs in HER2-positive SCLC [118].

miRNA-1 is a tumor suppressor that is highly conserved and targets multiple pathways, including members of the tyrosine kinase receptor family such as c-met and EGFR [119]. The down-regulation of miRNA-1 expression has been associated with a variety of malignancies, including ovarian cancer, colorectal cancer, squamous cell carcinomas from different origins, osteosarcoma, prostate cancer, gastric cancer, lung cancer, and rhabdomyosarcoma [120‐129]. These malignancies exhibit an up-regulation of the aforementioned tyrosine kinase receptors, contributing to the importance of miRNA-1 in their development and progression.

The significance of these alterations and their role in the development and advancement of malignancies has prompted the conduction of studies exploring the potential use of these non-coding RNAs as biomarkers and treatment approaches, yielding promising results. In addition to the studies discussed in this section, Table 1 provides a comprehensive summary of the most extensively investigated miRNA-based biomarkers. Moreover, Table 2 highlights some of the therapeutic applications of miRNAs that have been investigated in these studies.

The limited effectiveness of current therapeutic interventions contributes to the unfavorable prognosis of HCC [130]. Synthetic miRNA antagonists or mimics, when administered intravenously, tend to accumulate in the liver and kidney. This characteristic renders liver cancer an appropriate model for evaluating the efficacy of miRNA-based therapeutic strategies [131, 132]. Biodistribution studies of nanoparticles indicate that a significant proportion of administered nanomaterials tend to accumulate in the liver prior to undergoing hepatic clearance, rendering it a favorable target for various delivery systems. In cases of liver cancer, miR-122, which is known for its high abundance and liver-specific expression, has been observed to be downregulated. Restoring miR-122 through the use of a lentiviral expression vector has been shown to inhibit invasion, tumorigenesis, and metastasis in vivo. The inhibition of HCC metastasis is achieved through the modulation of ADAM17 and cyclin G1 by miR-122 [133, 134]. On the other hand, the expression of miR-21 is significantly upregulated in HCC. Inhibition of miR-21 in cultured HCC cells leads to increased expression of the PTEN tumor suppressor and decreased tumor cell proliferation, migration, and invasion [135, 136].

Lung cancer is a prominent contributor to cancer-associated mortality worldwide, with 5-year survival rates ranging from 4 to 17%. Liposomes derived from lung surfactants offer a practical option for delivering drugs to the lungs, making them suitable vehicles for miRNA-targeting agents. The downregulation of miR-34a, a miRNA known for its tumor suppressor function, has been observed in different types of solid tumors, including lung cancer. A study conducted by Wiggins et al. demonstrated that the administration of synthetic miR-34a encapsulated in liposomes effectively suppressed tumor growth in mice with NSCLC. Importantly, this treatment approach exhibited no signs of immunogenicity or toxicity. These findings align with prior in vitro studies conducted on genetic variations of NSCLC cell lines, which demonstrated that miR-34a decreased cell proliferation and the formation of cell colonies through the p53 pathways [137, 138]. Kasinski et al. introduced a novel approach involving the utilization of NOV340 liposomes for the concurrent delivery of tumor suppressors miR-34 and let-7b in NSCLC. The implementation of this method led to a notable 40% improvement in the survival rate of mutant mice [139]. Furthermore, the utilization of miR-200c loaded-NOV340 liposomes has been shown to augment the radiosensitivity of lung cancer cells through the upregulation of oxidative stress response mechanisms and inhibiting DNA double-strand breaks caused by radiation [140].

In 2013, the initial phase of clinical testing involved the administration of MRX34, which consisted of miR-34 mimics enclosed within NOV340 liposomes. This therapeutic approach represented the first instance of utilizing miRNA for therapeutic purposes. Nevertheless, the study was terminated in 2016 as a result of the occurrence of significant unfavorable incidents among the participants [141, 142]. The research conducted by Wu et al. revealed that cationic lipoplexes based on DOTMA demonstrated a high level of efficacy in transporting miR-29b to both NSCLC cells and xenograft mouse models. Following a series of repeated administrations, the mice exhibited a notable decrease in tumor dimensions and a substantial increase in miR-29b expression, reaching a five-fold amplification specifically within the tumor tissue. This observation indicates that the release of miR-29b from DOTMA lipoplexes is highly effective [143]. In a phase I clinical trial, nonliving bacterial nano-cells were employed as vehicles for the administration of miR-16 to patients with NSCLC. The system specifically targeted cancer cells expressing EGFR, resulting in inhibited tumor growth. Nevertheless, there were documented toxicities that were dependent on the dosage, such as anaphylaxis, inflammation, and cardiac events. The study recorded varying response rates, with 5% of participants exhibiting partial response, 68% experiencing stable disease, and 27% demonstrating progressive disease [144].

Given that HER-2 positive breast cancers constitute approximately 30% of cases characterized by an unfavorable prognosis, there is an increasing focus on effectively targeting this overexpressed receptor. Within this particular framework, experiments conducted on live mice with breast cancer have shown that the introduction of the tumor suppressor miR-125a-5p through lentiviral delivery resulted in a decrease in tumor development, metastasis, and vasculature. This effect was achieved by specifically targeting histone deacetylase 4 (HDAC4). Hayward et al. demonstrated that introducing miR-125a-5p into hyaluronic acid (HA)-coated liposomes effectively suppressed the HER-2 proto-oncogene in 21MT-1 breast cancer cells through transfection. Consequently, the inactivation of the MAPK and PI3K/AKT signaling pathways led to decreased migratory and proliferative capabilities [145, 146]. The utilization of HA/miRNA nanoparticles has shown potential in the context of targeted clinical interventions for breast cancer. The study by Deng et al. employed HA-chitosan nanoparticles for the simultaneous encapsulation of doxorubicin and miR-34a, resulting in an improved response to chemotherapy and a reduction in cancer cells migration [147, 148]. The in vivo experiments demonstrated a significant 58% decrease in tumor volume upon the incorporation of miR-9, miR-21, and miR-145 sponges into magnetic particles within PEI particles [149, 150]. The study conducted by Panebianco et al. discovered that the utilization of silica nanoparticles facilitated the delivery of miR-34a into mammary tumors, resulting in reduced tumor growth in mice. The diminished expression of target genes, such as c-Myc, served as an indicator of the biological efficacy of the administered miR-34a [137].

lncRNAs are a class of regulatory molecules that are longer than 200 nucleotides with a fundamental role in gene expression through their interaction with chromatin, transcriptional machinery, and other cellular components. Their biogenesis begins with transcription, predominantly by RNA polymerase II, similar to messenger RNAs (mRNAs). The initial transcripts, known as primary lncRNAs (pri-lncRNAs), often undergo splicing, polyadenylation, and capping [154]. However, lncRNA transcripts can exhibit unique features, such as variable splicing and less efficient polyadenylation, which can impact their stability and cellular localization [155]. Following successful processing, mature lncRNAs participate in various cellular processes. For instance, nuclear lncRNAs can interact with chromatin and transcription factors, thereby affecting transcriptional regulation [156]. Cytoplasmic lncRNAs, on the other hand, can modulate mRNA stability or translation, interact with miRNAs, or influence signal transduction pathways [157] (Fig. 3).

Regarding the interaction between lncRNA and microRNAs in promoting RTK expression, extensive research has been conducted in various types of cancer, such as colon, gastric, breast, osteosarcoma, HCC, and NSCLC [158‐161]. For instance, lncRNA XIST has been found to upregulate RTK family member, AXL, via sponging miR-93-5p, resulting in the overexpression of hypoxia-inducible factor 1-alpha (HIF1A). Ultimately, this process participated in enhancing the tumorigenesis capacity in colon cancer cells [162]. On the other hand, lncRNA XIST expression can also be involved in the upregulation of RTK-like orphan receptor 1 (ROR1) by sponging miR-30a-5p, leading to promoting cellular growth [163]. Another study demonstrated that ERBB4, a member of the RTK family, is modulated by lncRNA, called Linc00152. Mechanistically, lncRNA Linc00152 regulates the expression of ERBB4 by targeting miR-193a-3p, which may hinder the sensitization of malignant cells toward oxaliplatin-based chemotherapy. Targeted downregulation of Linc00152 expression significantly reduces chemoresistance in malignant cells, suggesting promising implications for developing novel therapeutic strategies [164]. Another lncRNA, known as H19, acts on the ubiquitin ligase E3 family by modulating miR-675 to promote RTK stability, thereby contributing to breast cancer development [165].

Furthermore, in neuroblastoma, lncRNA MALAT1 has been discovered to promote cellular invasion and migration via upregulating AXL, an RTK member. Inhibition of AXL has emerged as a promising therapeutic approach [166]. Similarly, the upregulation of a novel lncRNA called CALIC has been identified to enhance colon cancer cell migration and metastasis through regulating AXL signaling [167]. Moreover, another investigation found that in anaplastic thyroid cancer, lncRNA MALAT1 overexpression can lead to the activation of the RTK signaling pathway via a cascade of intermediary cellular signaling pathways, offering a remarkable diagnostic advantage [168]. In breast cancer, lncRNA MAYA has been found to play a role in bone metastasis. Regarding the underlying mechanism, it has been demonstrated that lncRNA MAYA can stimulate the formation of a heterodimeric complex consisting of ROR1, HER3, and the other RTKs, which subsequently activate signaling cascades and contribute to cancer cell migration [169]. Another lncRNA, SPRY4-IT1, has been shown to regulate the expression of the RTK family member FGFR2 by interacting with chromatin and regulating the expression of nearby genes. Additionally, SPRY4-IT1 has a regulatory effect on EMT, which is considered an essential mechanism in cell migration [170].

In addition to lncRNAs, which act as activators of the RTK signaling pathway, there are several lncRNAs with inhibitory effects on RTK regulatory pathways, resulting in the suppression of tumor development and progression. For example, a lncRNA named LINC00526 could function as a tumor suppressor that establishes a negative feedback loop with AXL, indicating its potential therapeutic application in glioma treatment [171]. Conversely, RTK can interfere with the functionality of lncRNAs, thereby impacting cancer metastasis. In breast cancer, for example, EGF has been found to decrease the expression of a newly discovered lncRNA called LIMT, which subsequently promotes tumor invasion [172]. Tumor-suppressing lncRNAs also restrict the invasive potential of melanoma and HCC by inhibiting RTK-related pathways [173]. Interestingly, Eph tyrosine kinase receptor A4 functions as a suppressor of the EMT process, in which lncRNA TUSC acts as a sponge to sequester miR-10a and increase Eph expression, thereby restricting tumor growth. This pathway exhibits similarities to previous studies but with the opposite effect [174].

On the other hand, it has been demonstrated that RTK inhibitors (RTKIs) are effective therapeutic agents for treating cancer. In this context, researchers have identified 45 lncRNAs that are differentially expressed in NSCLC cells, which are resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). The downregulated LINC01128, acting as a specific miRNA sponge, decreases PTEN via sponging miR-25-3p. This activates the PI3K/Akt signaling pathway and promotes EGFR-TKI resistance. Another lncRNA, HIF1A-AS2, has been shown to be downregulated by RTKIs, resulting in reduced tumor growth in NSCLC [175]. HIF1A-AS2 also regulates the expression of specific genes involved in angiogenesis, such as VEGFA, by interacting with specific proteins. By inhibiting HIF1A-AS2 expression, RTKIs can also indirectly decrease the expression of these angiogenic factors, further inhibiting tumor growth [176]. Similarly, a study investigated the potential of a lncRNA called growth arrest-specific 5 (GAS5) in improving the efficacy of EGFR-TKIs in NSCLC therapy. The results showed that GAS5 is downregulated in lung adenocarcinoma tissues, and lower expression levels are associated with larger tumor sizes, poor differentiation, and advanced pathological stages. Furthermore, overexpression of GAS5 sensitizes resistant NSCLC cells to EGFR-TKIs and inhibits tumor growth in mice treated with gefitinib. These findings suggest that GAS5 may be a potential biomarker for diagnosing lung adenocarcinoma and a possible therapeutic target to reverse EGFR-TKI resistance [177]. Moreover, the lncRNA H19 has been shown to be involved in the regulation of the EGFR signaling pathway. H19 regulates EGFR signaling by binding to the EGFR protein and promoting its degradation. Therefore, lncRNA H19 may play a key role in the response of cancer cells, such as NSCLC, to EGFR-TKIs. Thereby, lncRNA H19 seems to be a key factor in regulating RTK signaling [178]. RTKIs with a similar effect on the mentioned pathways on UCA1 [179], CRNDE [180], and PCAT1 [181] genes lead to the development of other types of NSCLCs. In an alternative mechanism, LncRNA-SARCC functions as a suppressor of the androgen receptor (AR) protein, hindering the propagation of its downstream signals involving AKT, MMP-13, K-RAS, and P-ERK. This obstruction leads to the inhibition of invasiveness in RCC cells while also enhancing their sensitivity to Sunitinib therapy. The findings of this investigation underscore the potential effectiveness of targeting LncRNA-SARCC and its underlying pathway as a viable therapeutic approach for treating RCC. It should be noted, however, that certain RTKIs have been shown to induce the expression of a group of lncRNA molecules, including LncRNA-SARCC, which are associated with improved prognosis and contribute to the restoration of cancer suppression in RCC [182]. Therefore, this evidence could imply that lncRNAs may play an essential role in regulating RTKs.

Altogether, lncRNAs play a crucial role in modulating RTK signaling pathways and the development of cancer. However, comprehensive investigations are necessary to elucidate the intricate mechanisms underlying lncRNA-mediated regulation of RTK signaling and to recognize potential therapeutic targets for improving RTK-associated diseases. Nonetheless, gaining a deeper understanding of these pathways offers a new approach to managing different types of cancer, highlighting the need for more comprehensive investigation (Tables 3, 4).