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Cancer stem cells (CSCs) have been identified in many types of cancer since their discovery in leukemia in the 1990s. CSCs have self-renewal and differentiation capacity, and are thought to be a key driver for the establishment and growth of tumours. Several intracellular signalling pathways are reported to play a significant role in the regulation of the biological activities of CSCs. Thus, many researchers have considered CSCs to be a compelling therapeutic target for cancer, and blockade of CSC-related signalling pathways can be efficacious for the treatment of multiple cancer types. This chapter succinctly summarises the recent progress in the development of treatments targeting signalling pathways related to the functions of CSCs.
New Wind Therapeutics L3C, Boston, United States of America
*Address all correspondence to: shin.mukai@new-wind-ther.com
1. Introduction
Cancer is a life-threatening disease in which abnormal cells grow and divide, resulting in the destruction of normal body tissues. The last several decades have seen advancements in cancer treatments [1]. However, the conventional therapeutic methods often fail due to cancer recurrence and metastasis [2]. This can be explained by the existence of cancer stem cells (CSCs), which are a minor population in tumours and can survive most traditional cancer therapies killing cancer cells with proliferative properties [3]. Cancer relapse, metastasis, multidrug resistance, and radiation resistance can be induced by the transient arrest of CSCs at the G0 phase, leading to the production of new malignant tumours [4]. The ability of CSCs to self-renew and differentiate into multiple cellular subtypes allows them to generate tumours [4]. Thus, researchers have regarded CSCs as a promising target for the treatment of cancer since they were discovered in leukemia in the 1990s [5, 6]. CSCs have also been found to be a subpopulation of many types of tumours, and tissue-specific expression of CSC markers has been reported [7]. It is known that the biological functions of CSCs are controlled by several signalling pathways [8]. This chapter focuses on the research status in cancer therapies targeting the signalling pathways that are believed to control the properties of CSCs.
Since CSCs were found in leukemia in the 1990s, they have been studied intensively [5, 6]. However, the origin of CSCs remains to be elucidated [9]. It has been reported that (a) CSCs possess self-renewal capacity and high proliferation rate, (b) CSCs are able to generate and maintain tumours, and (c) cancer recurrence may be induced by the unlimited self-renewal capacity of CSCs [10]. CSCs are shown to be a distinct subpopulation in haematologic malignancies and solid tumours, and cell surface markers of CSCs in various types of cancer have been reported and can be used for the identification and isolation of CSCs (Figure 1) [11, 12, 13, 14, 15]. Signalling pathways such as Wnt/β-catenin, Notch and Hedgehog signalling pathways are thought to regulate the properties of CSCs [8]. Emerging evidence supports the clinical relevance of CSCs [16]. In particular, CSCs are shown to be resistant to conventional chemotherapy and radiation therapy, and they are believed to be a key player for cancer recurrence and metastasis [16]. Thus, understanding of signalling pathways that control the functions of CSCs can be useful for the creation of novel therapeutic interventions for cancer.
Figure 1.
Cell surface markers for CSCs in various organs. This figure was created with BioRender.
3. Development of therapeutic modalities targeting CSCs
3.1 Notch signalling
The Notch signalling pathway is a highly conserved pathway in mammals and controls a variety of cellular functions [17]. In mammals, the Notch pathway comprises four Notch receptors (Notch 1–4) and five Notch ligands (Jagged 1, Jagged 2, Delta-like ligand (DLL)-1, DLL-3, and DLL-4), and its primary effector is the transcription factor CSL (CBF1/RBP, Su(H)/Lag-1), which is crucial for the activation of the genes downstream of the Notch signalling pathway [18]. The Notch signalling pathway is divided into canonical and noncanonical pathways: the CSL-dependent pathway (canonical Notch signalling pathway) and non-CSL-dependent pathway (non-canonical Notch signalling pathway) [19]. Evidence suggests that these pathways play an instrumental role in preserving the existence of stem cells and initiating embryonic or foetal cell differentiation [20].
In the canonical Notch signalling pathway (Figure 2), the binding of receptor and ligand is induced through metalloproteinase- and γ-secretase-mediated proteolytic activation of the Notch receptor, leading to the release of the intracellular NOTCH domain (NICD) [21]. Subsequently, NICD migrates to the nucleus and forms a complex with CSL. As a result, the transcription and expression of the downstream target genes are triggered, leading to self-renewal, differentiation and proliferation [21].
Figure 2.
Brief diagram of the canonical Notch signalling pathway. This figure was created with BioRender.
Recent studies suggest that there is non-canonical Notch signalling, which can be activated either with or without ligand interaction [22]. In addition, the activation of non-canonical Notch signalling can occur in a γ-secretase-dependent or -independent manner [22]. In the case where non-canonical Notch signalling occurs in a γ-secretase-independent way, Notch remains bound to membrane [22]. Non-canonical Notch signalling does not require CSL [23, 24]. Instead, NICD or membrane bound Notch interacts with (a) Wnt, PI3K, mTORC2 and/or AKT pathways in the cytoplasm, and (b) NF-κB, YY1 and/or HIF-1α pathways in the nucleus [23, 24]. It is suggested that non-canonical Notch signalling plays a role in cell survival, metabolism and differentiation [23, 24]. Compared with the canonical Notch signalling pathway, there is less information on the non-canonical Notch signalling pathway [25]. Thus, more work will be needed for the identification of potential therapeutic targets in the non-canonical Notch signalling pathway [25].
Notch inhibition is believed to be a promising therapeutic approach to target CSCs, which are resistant to conventional methods such as chemotherapy and radiation [26]. As γ-secretase is a key player in Notch signalling, a great deal of effort has been invested in the development of γ-secretase inhibitors (GSIs) (Figure 3) [27]. It should be noted that GSIs show anti-CSC effects and that they were the first Notch inhibitors to reach clinical development [27]. However, one of the major concerns is the toxicity of GSIs [28]. In particular, serious toxicity in the gastrointestinal tract can be caused by GSIs [28]. Several GSIs have entered clinical trials thus far. Data from a Phase II clinical trial suggest that RO4929097 did not show sufficient efficacy for the treatment of metastatic melanoma and platinum-resistant ovarian cancer as monotherapy [29, 30]. Nirogacestat (PF-3084014) is another GSI undergoing clinical trials for desmoid tumours [31]. The result of Phase II clinical trials indicates that (a) treatment of desmoid tumour fibromatosis patients with Nirogacestat could be a promising approach, (b) the objective response rate was 71.4% and (c) relatively low doses and high tolerability were achieved, resulting in prolonged disease control [31, 32]. Another study shows the antitumour and antimetastatic effects of Nirogacestat in hepatocellular carcinoma [33]. The potent pan-Notch Inhibitor BMS-906024 has advanced into clinical trials, and the data suggest that it could be effective for the treatment of leukemia and solid tumours [34]. The clinical development status of other small molecule inhibitors is as follows: (a) The GSI MK-0752 is in a Phase I clinical trial for the treatment of pancreatic ductal adenocarcinoma [27], (b) the GSI LY900009 is in a Phase I clinical trial for ovarian cancer [35], (c) CB-103, which inhibits the interaction between NICD and CSL, is in a Phase I clinical trial for adenoid cystic carcinoma (ACC), colorectal cancer, breast cancer and prostate cancer [36], and (d) Crenigacestat (LY3039478), which is an oral Notch and GSI inhibitor, is in a Phase I clinical trial for solid tumours [37]. Recently, cryoelectron microscopy (cryo-EM) structures of γ-secretase in complex with each of the two GSI clinical candidates Semagacestat and Avagacestat have been reported, and these pieces of information might be useful for the design of novel GSIs [38].
Figure 3.
Structures of Notch signalling inhibitors in clinical development.
A study suggests that the expression of the Notch ligand DLL4 is increased in gastric cancer, enhancing self-renewal ability of CSCs [39]. Therefore, inhibition of DLL4 can be an effective approach to treating cancer [39]. Currently, Enoticumab (REGN421), a fully human IgG1 monoclonal antibody against DLL4, is in a phase I clinical trail for the treatment of solid tumours [40].
3.2 Wnt signalling
The Wnt signalling pathway is known to play a pivotal role in embryogenesis and tissue repair by controlling proliferation, differentiation, apoptosis and cell-to-cell interactions [41, 42]. The Wnt signalling pathway is classified into the canonical Wnt pathway (β-catenin dependent) and the noncanonical Wnt pathway (β-catenin independent) [43]. Wnt ligands are required for the activation of Wnt signalling, and the acyltransferase Porcupine is known to be essential for the production of Wnt ligands [44]. In canonical Wnt signalling (Figure 4), the absence of Wnt ligands leads to the degradation of β-catenin due to phosphorylation by glycogen synthase kinase 3β (GSK3β), and thereby translocation of β-catenin from the cytoplasm to the nucleus does not occur [45]. In the presence of Wnt ligands, their ligation to Frizzled proteins and LRP5/6 receptors induces the activation of the cytoplasmic protein DVL and the subsequent suppression of GSK3β [46]. It enables β-catenin to migrate to the nucleus and trigger target gene transcription by binding to TCF/LEF transcription factors [46]. Noncanonical Wnt signalling does not require the cytoplasmic stabilisation of β-catenin or its translocation into the nucleus [47]. The noncanonical Wnt signalling is subdivided into the following two well-characterised pathways: the planar cell polarity (Wnt/PCP) pathway and the Wnt-Calcium (Wnt/Ca2+) pathway [48]. In the Wnt/PCP pathway, Wnt ligands bind to the Frizzled receptor, leading to the activation of Dishevelled (DVL) protein [49]. Activated DVL forms the DVL-Rac complex and DVL-Rho complex [49]. The former stimulates the Rho kinase (ROCK), and the latter stimulates the c-Jun N-terminal Kinase (JNK) [50]. JNK is known to translocate into the nucleus and trigger the transcription of target genes [51]. The Wnt/Ca2+ pathway involves the activation of PLC and PKC, and an increase in intracellular Ca2+ [52]. The phosphatase calcineurin is stimulated by Ca2+ and dephosphorylates the transcriptions factor NF-AT, resulting in the migration of NF-AT to the nucleus [52].
Figure 4.
Brief diagram of the canonical Wnt signalling pathway. This figure was created with BioRender.
Dysregulation of Wnt signalling is observed in many types of cancer [53]. The Wnt signalling cascade is reported to play an important role in controlling the properties of CSCs [53]. Thus, many scholars have been striving to create therapeutic modalities to target Wnt signalling for safe and effective elimination of CSCs, and several small molecule inhibitors and monoclonal antibodies have entered clinical trials (Figure 5) [53]. Evidence suggests that pharmacological inhibition of Porcupine can selectively block Wnt signalling and suppress tumour growth [54]. Thus, Porcupine is considered to be a promising therapeutic target for cancer [54]. LGK-974, a small molecule disrupting the enzymatic activity of Porcupine, is currently in Phase I clinical trials for pancreatic cancer, melanoma and triple-negative breast cancer [55]. Cryo-electron microscopy (cryo-EM) structures of Porcupine in complex with LGK-974 are available in the PDB database (PDB ID: 7URD) [55], and this information could be useful for creation of novel Porcupine inhibitors. Another Porcupine inhibitor ETC-159 is in a Phase I clinical trial for the treatment of solid tumours [56]. The small molecule inhibitor PRI-724 is reported to block canonical Wnt signalling by preventing the interaction between β-catenin and its coactivator CREB binding protein (CBP) [57]. PRI-724 is in a Phase II clinical trial for advanced myeloid malignancies [58]. The therapeutic monoclonal antibody OMP-18R5 (vantictumab), which can target the Frizzled receptors, is now in a Phase I clinical trial for the treatment of non-small-cell lung cancer (NSCLC), pancreatic cancer and breast cancer [59, 60, 61, 62]. The recombinant fusion protein ipafricept (OMP-54F28) can inhibit Wnt signalling by binding to Wnt ligands, and its safety and effectiveness are being evaluated in clinical trials [63, 64, 65].
Figure 5.
Structures of Wnt signalling inhibitors in clinical development.
3.3 Hedgehog signalling
The Hedgehog (Hh) signalling pathway contributes to the control of cell proliferation, cell survival, cell differentiation, and stem cell maintenance and development [66]. In Hh signalling (Figure 6), the autoproteolytic cleavage of Hh ligand precursor proteins leads to the production of an N-terminal protein, followed by dual lipid modification [67]. Subsequently, active Hh ligands are released through mediation of Dispatched and Scube2 [67]. In the absence of Hh ligand, Patched (PTCH) prevents the activation and ciliary localisation of Smoothened (SMO) [68, 69]. As a result, the Glioma-Associated Oncogene Homolog (GLI) forms a complex with Suppressor of Fused (SUFU), which precludes GLI from translocating into the nucleus [68, 69]. In the presence of Hh ligand, the binding of Hh to PTCH allows SMO to interact with β-arrestin (Arrb2) and kinesin family member 3A (KIF3A), leading to the ciliary localisation of SMO [68, 69]. As a result, GLI is released from SUFU and subsequently migrates to the nucleus, triggering the transcription of Hh target genes [68, 69].
Figure 6.
Brief diagram of the canonical Hedgehog signalling pathway. This figure was created with BioRender.
Evidence suggests that the dysregulation of Hh signalling is associated with detrimental events such as the self-renewal and metastasis of cancer stem cells [67]. Thus, therapeutic targeting of Hh signalling has accorded a great deal of attention from many researchers, and SMO has been regarded as the most promising pharmacological target [68]. Indeed, several SMO inhibitors have been approved by the Food and Drug Administration (FDA) or are undergoing clinical trials (Figure 7) [70]. Vismodegib (GDC-0449) was the first SMO inhibitor that was granted FDA approval to treat basal cell carcinoma in 2011 [71]. Mounting evidence suggests the inhibitory activity of Vismodegib against self-renewal and mammosphere formation of breast CSCs [72]. Data from Phase II clinical trials demonstrate that (a) Vismodegib could be used as a neoadjuvant chemotherapy agent for patients with triple-negative breast cancer (NCT02694224) [73], (b) Vismodegib could be efficacious for the treatment of pancreatic cancer by suppressing self-renewal, proliferation and survival of pancreatic CSCs [74] and (c) Vismodegib could be effective for untreated metastatic colorectal cancer by reducing the stem cell markers of colon CSCs [75, 76]. These results support the notion that Vismodegib can inhibit the activities of CSCs by blocking the Hh signalling pathway. The SMO inhibitor Sonidegib (LDE225) was approved by FDA for the treatment of advanced basal cell carcinoma in 2015 [77]. A recent study indicates that Sonidegib can make triple-negative breast cancer more sensitive to Paclitaxel and improve clinical outcomes by reducing the expression of CSC markers [78]. Glasdegib (PF-04449913) was an FDA-approved SMO antagonist for the treatment of acute myeloid leukemia and launched in the USA in 2018 [79]. Glasdegib is also undergoing a Phase II clinical trial for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia [80]. Although the development of SMO inhibitors is beneficial for cancer patients, monotherapy with each of the FDA-approved antagonists can cause SMO mutations in tumour tissues, leading to drug resistance [80]. Hence, novel therapeutic methods inhibiting SMO will need to be created in order to overcome this setback. The clinical development status of other SMO inhibitors is as follows [81]: (a) BMS-833923 is in a Phase I clinical trial for extensive-stage small cell lung cancer [82], (b) Itraconazole is in a Phase II clinical trial for prostate cancer [83], (c) Saridegib (IPI-926) is in a Phase I clinical trial for advanced and/or metastatic solid tumours [84], (d) LEQ-506 is in a Phase I clinical trial for advanced solid tumours [85], (e) Taladegib (LY2940680) is in a Phase I clinical trial for advanced solid tumours [86] and (f) TAK-441 is in a Phase I clinical trial for advanced nonhematologic malignancies [87]. In addition to the SMO inhibitors, arsenic trioxide is reported to inhibit the Hh signalling pathway and tumour growth by binding to GLI [81]. Arsenic trioxide is in a Phase II clinical trial for the treatment of advanced neuroblastoma or other childhood solid tumours [88]. Although there are no other GLI inhibitors undergoing clinical trials, in vitro and in vivo preclinical investigation into the GLI inhibitor GANT61 suggests its inhibitory activity against pancreatic cancer stem cells [89].
Figure 7.
Structures of Hedgehog signalling inhibitors in clinical development.
3.4 NF-κB signalling
The transcription factor nuclear factor kappa B (NF-κB) is a rapidly inducible transcription factor and a family of heterodimers or homodimers [90]. The heterodimers or homodimers are produced from different combinations of the five related proteins: p65/RelA, RelB, c-Rel, p105/p50 (NF-κB1) and p100/p52 (NF-κB2) [90]. The p50/p65 complex is thought to the most abundant form of NF-κB and serve main physiological functions [91]. The activation of NF-κB signalling induces the translocation of the transcription factor complexes from the cytoplasm to the nucleus [92]. The NF-κB signalling pathway diversifies into the canonical NF-κB signalling pathway and the noncanonical NF-κB signalling pathway [92]. The canonical NF-κB pathway is activated by the binding of ligands to their receptors such as the binding of (a) bacterial cell components to toll-like receptors (TLRs), (b) TNF-α to the TNF receptor (TNFR), (c) lipopolysaccharides to their respective receptors such as TLRs and (d) IL-1β to the IL-1 receptor (IL-1R) [93]. In response to the stimulation of these receptors, the kinase TGFβ-activated kinase 1 (TAK1) is activated, leading to the subsequent phosphorylation and activation of the IκB kinase (IKK) proteins [94]. The activated IKK proteins then phosphorylate IκB proteins. It induces the degradation of IκB, leading to the translocation of the activated p50/p60 complex into the nucleus [95]. The noncanonical NF-κB pathway is initiated by stimulation of receptors such as CD40, receptor activator for NF-κB (RANK), B cell activation factor (BAFF), TNFR2 and lymphotoxin β-receptor (LTBR) [94]. Subsequently, the kinase NF-κB-inducing kinase (NIK) is activated, resulting in the phosphorylation and activation of IKKα [94], which induces the phosphorylation of carboxy-terminal serine residues of p100 [94]. As a result, the C-terminal IκB-like structure of p100 is selectively degraded, which generates p52 and causes the p52-RelB complex to migrate to the nucleus [94].
A previous study shows that the production of cytokines, growth and angiogenic factors and proteases is promoted in the tumour development and progression, activating NF-κB signalling [96]. The NF-κB pathway is reported to contribute to self-renewal, maintenance and metastasis of CSCs [11]. Ovarian CSCs can display the enhanced capability of self-renewal, metastasis and maintenance due to the increased expression of RelA, RelB and IKKα [97]. In breast cancer, NIK expression is augmented, and the noncanonical NF-κB pathway is activated, leading to the self-renewal and metastasis of breast CSCs [98]. Regarding the development of therapeutic modalities to inhibit self-renewal, proliferation and metastasis of CSCs by targeting the NF-κB pathway (Figure 8A), Disulfiram is known to inhibit the activity of NF-κB in breast CSCs and is in a Phase II clinical trial for the treatment of metastatic breast cancer [99, 100]. Sulforaphane is suggested to prevent the translocation of p50/p65 and reduce the expression and transcriptional activity of p52/RelB, resulting in the inhibition of self-renewal of triple-negative breast CSCs [101]. Sulforaphane is in a Phase II clinical trial for the treatment of breast cancer [102]. The NF-κB pathway inhibitor curcumin is reported to impede self-renewal and metastasis of CSCs and is undergoing clinical trials for the treatment of breast cancer [103, 104, 105].
Figure 8.
Structures of CSC-related signalling inhibitors in clinical development. (A) NF-κB, (B) mTOR, (C) JAK/STAT, (D) ROCK.
3.5 mTOR signalling
The mammalian target of rapamycin (mTOR) signalling pathway plays a pivotal role in cellular growth and metabolism in mammalian cells within various environments [106]. The activation of mTOR signalling can promote cell survival by (a) increasing cellular metabolism and the synthesis of proteins and lipids and (b) blocking apoptotic pathways [106]. The mTOR pathway is initiated by the binding of growth factors to tyrosine kinase receptors in the cell membrane, leading to the phosphorylation and activation of phosphatidylinositol 3-kinase (PI3K) [107]. Subsequently, protein kinase B (AKT) is phosphorylated and activated, leading to the activation of mTOR [107]. It activates a variety of transcription factors and enables them to migrate to the nucleus in order to promote the transcription of the target genes [108]. mTOR is divided into two protein complexes. mTORC1 is a complex of RAPTOR, mLST8, PRAS40 and DEPTOR, and mTORC2 is a complex of RICTOR, mLST8, DEPTOR, mSin1 and PROCTOR [109, 110]. mTORC1 is reported to (a) activate the ribosomal protein S6K, which promotes protein synthesis, (b) facilitate lipid synthesis and mitochondrial biogenesis and (c) reduce autophagy [109, 110]. mTORC2 is known to promote actin cytoskeleton and cell migration by phosphorylating various proteins [109, 110].
Evidence suggests that the mTOR signalling pathway is correlated with the functions of CSCs. According to previous studies, activation of mTOR signalling contributes to (a) prostate cancer radioresistance due to the enhancement of CSC properties and (b) the tumourigenicity of breast CSCs [111, 112]. Dysregulation of the PI3K/Akt/mTOR signalling pathway is reported to enhance the expression of chemokine (C-X-C motif) receptor 4 (CXCR4), and CXCR4-mediated STAT3 signalling is then activated, promoting the self-renewal of CSCs in non-small-cell lung cancer [113]. Furthermore, the activity of mTOR through the PI3K feedback loop is associated with the survival of prostate CSCs [114].
The mTOR signalling pathway has been regarded as a promising candidate for therapeutic modalities targeting CSCs, and several mTOR inhibitors have been approved for the treatment of cancer or undergoing clinical development (Figure 8B) [115]. As demonstrated by a series of in vitro and in vivo experiments, the mTOR inhibitor Everolimus can suppress the expression and phosphorylation of AKT-1, and thereby inhibit the activity of HER2-overexpressing breast CSCs [116]. Everolimus has been approved by FDA for the treatment of advanced breast cancer [117]. The mTOR inhibitor Rapamycin is shown to suppress the properties of colon CSCs [118] and inhibit the stemness of haemangioma stem cells [119]. Rapamycin is undergoing clinical trials for advanced or metastatic colorectal cancer and infantile hepatic haemangioendothelioma [120, 121]. Previous reports show the inhibitory effects of the mTOR antagonist Metformin on breast and pancreatic CSCs [122, 123]. Clinical trials of Metformin are in progress or completed for the treatment of breast and pancreatic cancer [124, 125]. Considering previous studies show that mTOR signalling plays an important role in controlling the functions of CSCs, further investigation into a link between mTOR signalling and CSCs could lead to the development of better therapeutic strategies for cancer.
3.6 JAK/STAT signalling
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway contributes to a variety of biological processes such as embryonic development, stem cell maintenance, haematopoiesis and inflammatory response [126]. It is known that the JAK family in mammals comprises four members (JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2)) and that the STAT family in mammals consists of seven members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) [127]. The JAK/STAT signalling pathway is initiated by the binding of cytokines to their corresponding receptors [128]. The receptors then undergo dimerisation, and the JAKs bound to the receptors come close to each other, leading to the activation of the JAKs through the interaction of tyrosine phosphorylation [128]. The activated JAKs induce the phosphorylation of the tyrosine residues of the catalytic receptor, resulting in the formation of a docking site with the SH2 domain of the STAT protein [128]. Subsequently, the STAT protein bound to the receptor is phosphorylated and dimerised, culminating in the translocation of the activated STAT to the nucleus and the transcription of the target genes [128].
Literature precedent indicates that JAK/STAT signalling plays a role in controlling the properties of CSCs [129]. It has been suggested that (a) the self-renewal and survival of breast CSCs are facilitated by the persistent activation of JAK/STAT signalling [112], (b) IL-10-mediated JAK1/STAT1 signalling promotes the self-renewal and migration of non-small-cell lung cancer and colorectal CSCs [130, 131], (c) the OCT4-activated JAK1/STAT6 pathway is associated with the functions of ovarian CSCs [132], (d) OCT4, which is a gene downstream of IL-6-mediated JAK1/STAT6 signalling, is involved in the transformation of bulk cancer cells to CSCs in breast cancer [133] and (e) JAK2/STAT3 signalling plays a role in the regulation of the properties of breast and colorectal CSCs [134, 135, 136].
With respect to the development of therapeutic strategies to target JAK/STAT signalling for the treatment of cancer, the JAK1/2 inhibitor Ruxolitinib is shown to inhibit the functions of CSCs, leading to a decrease in the number of CSCs (Figure 8C) [137]. Ruxolitinib is undergoing clinical development for the treatment of solid tumours [138]. Many studies have shown that the JAK/STAT signalling pathway is correlated with the survival, self-renewal and metastasis of CSCs. Thus, more endeavours will be needed to develop novel therapeutic modalities targeting CSCs through the inhibition of JAK/STAT signalling.
3.7 ROCK signalling
The Rho-associated coiled-coil-containing protein kinase (ROCK) signalling pathway plays a pivotal role in various cellular activities such as cell survival and apoptosis [139]. It is known that there are two types of ROCK in mammals: ROCK1 and ROCK2 [139]. Diverse extracellular stimuli activate guanine nucleotide exchange factors (GEFs), leading to the conversion of Rho-GDP to Rho-GTP [140]. Rho-GTO subsequently activates ROCK1 and ROCK2, resulting in the phosphorylation of their substrates and the induction of a range of cellular responses [140].
Dysregulation of ROCK signalling is reported to be involved in the pathogenesis of a variety of diseases such as cancer [139]. According to an in vitro study, the properties of CSCs can be reduced by pharmacological inhibition of ROCK with the ROCK inhibitors ML7 or Y-27632, supporting the involvement of ROCK signalling in controlling the functions of CSCs [141]. With regard to the clinical development of ROCK inhibitors, the dual ROCK1/2 antagonist AT13148 is undergoing clinical trials for patients with advanced cancer [142, 143]. There is still sparce information on the roles of the ROCK signalling pathway in the regulation of the functions of CSCs. Thus, further investigation into a correlation between ROCK signalling and CSCs could be beneficial for the development of novel cancer treatments.
3.8 TGF-β signalling
The transforming growth factor β (TGF-β) signalling pathway contributes to diverse biological processes including cell proliferation and differentiation [11]. When dimeric TGF-β binds to the TGF-β receptor type-2 (TβRII), TβRII is dimerised with the TGF-β receptor type-1 (TβRI), leading to the phosphorylation and activation of the receptor-regulated SMADs (R-SMADs) SMAD2 and SMAD3 [11]. Subsequently, SMAD2 and SMAD3 undergo trimerisation with the common-partner SMAD, SMAD4 [11]. The trimer migrates to the nucleus and promotes the transcription of target genes [11].
It has been suggested that TGF-β may have contradictory functions in the properties of CSCs [144]. A study using a breast cancer xenograft model indicates that the activation of TGF-β signalling can reduce the number and the self-renewal potential of breast CSCs [145]. In addition, another in vivo study suggests that the number of CSCs in diffuse-type gastric carcinoma can be reduced by the activation of TGF-β signalling, leading to the suppression of tumour formation [146]. In contrast, it is reported that the activation of TGF-β signalling leads to an increase in CSC counts and the enhancement of CSC properties in various types of cancer such as breast cancer liver cancer, gastric cancer, skin cancer, glioblastoma and leukaemia [147, 148, 149, 150, 151, 152, 153, 154, 155, 156]. Considering these pieces of evidence, the therapeutic targeting of the TGF-β signalling pathway might be a promising strategy to eliminate CSCs. However, more work will be required to gain a better understanding of a link between TGF-β signalling and CSCs for the development of novel therapeutic modalities.
CSCs are a minor population in tumours, and their self-renewal capacity and differentiation potential contribute to tumour relapse, metastasis, chemoresistance and radioresistance. This chapter has provided a succinct summary of (a) major signalling pathways that are reported to be associated with the functions of CSCs and (b) clinical development of inhibitors targeting CSC-related signalling pathways for the purpose of encouraging research scientists (medicinal chemists, biologists, immunologists and others) to create new treatments (Table 1). Therapeutic targeting of CSCs via these signalling pathways has been considered to be a compelling strategy, and several small molecule inhibitors such as Vismodegib (GDC-0449), Sonidegib, Glasdegib (PF-04449913) and Everolimus have been approved by FDA for the treatment of cancer in the clinic. However, the development of such therapeutic interventions is challenging, and there is still vast scope for improvement. It is in part because signalling pathways interact with each other and because the CSC properties are thought to be controlled by the signalling network. AL/ML has been applied to the drug discovery, and it is reported that AL/ML is highly beneficial for target discovery, drug design and so on. These pieces of evidence can provide a scientific rational for applying AL/ML to the development of new therapeutic interventions targeting CSCs. The signal regulatory mechanisms of CSCs remain to be elucidated, and continuing studies of CSC-related pathways will lead to the creation of novel therapeutic modalities for various types of cancer.
Table 1.
Landscape of clinical development of inhibitors targeting CSC-related pathways.
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Written By
Shin Mukai
Submitted: 06 October 2022Reviewed: 09 November 2022Published: 24 December 2022
Open access peer-reviewed chapter
