MYC: Master Regulator of Cell Death and Tumor Progression

1. Introduction

MYC gene, which locates on chromosome 8q24.21, is responsible for codifying the transcription factor MYC [1, 2]. MYC represents one of the more widely and influential oncogenes in cellular and tumor biology, because of its involvement in a multitude of vital processes [2]. The codified protein belongs to the bHLH-LZ (basic helix-loop-helix leucine zipper) family of transcription factors, including also N-MYC and L-MYC. It regulates the expression of an extraordinary number of genes, estimated to be approximately 15% of the human genome [3]. MYC activates or represses genes involved in vital activities such as cell proliferation, protein synthesis, energy metabolism, DNA repair, and the cell cycle by building complexes with the MAX protein and binding to certain DNA regions known as E-boxes [4]. Under physiological conditions, MYC acts as a mediator of cellular responses to external stimuli, such as growth factors and mitogenic signals (Figure 1) [5, 6]. This function allows cells to adapt their growth and division to the needs of the surrounding tissue, maintaining a dynamic balance between proliferation and differentiation [5]. However, when MYC expression or activity is dysregulated, as frequently occurs in tumors, a cascade of pathological events occurs that favor uncontrolled growth and aberrant survival of cells (Figure 1) [7]. One of the many characteristics of MYC is its dual role in programmed cell death or apoptosis [8]. Under physiological conditions, MYC promotes cell survival and proliferation, but under stress conditions it can activate potent apoptotic pathways that lead to the elimination of damaged cells (Figure 1). This dual role makes MYC not only a growth promoter, but also a guardian against uncontrolled proliferation [9, 10]. At the molecular level, MYC activates apoptotic pathways by interacting with key proteins, such as p53, a major tumor suppressor [11]. Under conditions of cellular stress, excessive MYC activity can induce the expression of pro-apoptotic genes, such as BCL-2-associated X protein (BAX) and p53 upregulated modulator of apoptosis (PUMA), while inhibiting anti-apoptotic proteins, such as B-cell lymphoma 2 (BCL-2). This delicate balance represents an intrinsic safety strategy: if MYC activity exceeds a critical threshold, cells are induced to die to avoid pathological proliferation. However, in tumors, this mechanism is frequently bypassed [12, 13]. Mutations or alterations in apoptotic pathways, such as the loss of p53, allow tumor cells to use the proliferative activity of MYC without suffering its apoptotic consequences [14]. MYC is deregulated in the vast majority of tumors, indeed its overexpression, caused by several genetic alterations, such as gene amplifications, chromosomal translocations, or aberrant transcriptional activation, is associated with the uncontrolled proliferation of tumor cells [5, 15]. MYC promotes tumor progression through uncontrolled cell proliferation, activating genes involved in the synthesis of nucleotides and proteins, allowing tumor cells to replicate in an uncontrolled manner, or promoting the consumption of glucose, an essential element for tumor growth [16]. Furthermore, its hyperactivation makes cells insensitive to antiproliferative drugs, also promoting the production of pro-angiogenic factors, such as vascular endothelial growth (VEGF), which support the development of new blood vessels [17]. These properties make MYC a central element in tumor progression, contributing not only to the primary growth of the tumor but also to the promotion of metastases and therapy resistance. The importance of MYC in tumorigenesis makes it a target of great interest for oncology research, but being a transcription factor and not having enzymatic pockets accessible to conventional drugs, its therapeutic targeting is extremely complex. However, there are innovative approaches, such as epigenetic therapies, that are opening new avenues for MYC targeting. In fact, direct inhibition of MYC could stop tumor growth and overcome resistance to existing treatments.

2. MYC structure and function

MYC, a proto-oncogene encoding a protein crucial in gene regulation, is considered one of the most important regulators of cell biology. It is a transcription factor that, by binding to specific DNA sequences called E-box: 5'-CACGTG-3′, activates or represses a lot of genes involved in different cellular processes [18]. MYC was originally identified in avian oncogenic viruses as a viral oncogene and named v-MYC. Its corresponding c-MYC was later recognized as essential for cell growth and proliferation in both normal and pathological conditions [19]. The MYC family consists of c-MYC, which plays a fundamental role in the regulation of the cell cycle and metabolism. It is the most studied and significantly expressed member of the family [20]; N-MYC, frequently amplified in neuroblastic tumors. It is the member mainly expressed in nervous tissues during embryonic development; L-MYC, involved in the regulation of cell proliferation in small cell lung cancer [21]. It is the member of the family whose functions are less understood than the others. The MYC genes, found in complex organisms, play a crucial role as a transcriptional regulator necessary for fundamental biological processes [22]. The three members of the MYC family exhibit significant similarities in regions that serve as docking points for various cofactors. These cofactors influence both the activity and stability of MYC, contributing to its oncogenic potential [23]. The conserved pattern known as the b-HLH-LZ motif, which is found in the C-terminal region of these proteins, is made up of a basic region (b), a helix-loop-helix (HLH), and a leucine zipper (LZ) domain. As seen in Figure 2, the b-region makes it easier to bind specific DNA sequences, whereas the HLH and LZ domains allow dimerization [24]. These motifs are crucial to create DNA-binding domain trough by MYC/MAX heterodimers [25, 26, 27]. Six domains known as MYC homology boxes (MBs) make up the N-terminal region of MYC proteins. The transactivation domain (TAD) contains the residues MB0 (residues 16–33), MBI (residues 45–65), and MBII (residues 128–144) (Figure 2). These domains are essential for preserving protein stability, allowing interactions between proteins, and regulating the transcriptional activation or repression of target genes [25, 28, 29]. MB0 interacts with transcription elongation factors and contributes to tumor progression, while MBI plays a role in regulating MYC degradation via the ubiquitin-proteasome pathway [29, 30]. MBII, the better characterized region within TAD, is essential for key MYC properties, including specific DNA binding, autoregulation, and transcriptional activity [28]. Transcription of MYC-bound genes can be activated through the recruitment of histone acetyltransferase (HAT) complexes by MBII binding to transformation/transcription domain-associated protein (TRRAP) [29, 31, 32]. In the central region of MYC, there are three additional conserved domains: MBIIIa, MBIIIb, and MBIV (Figure 2). MBIIIa interacts with histone deacetylases (HDACs) and is involved in gene repression mediated by MYC, while MBIV contributes to DNA binding, though its precise mechanism remains unclear [33]. MBIIIb interacts with WD repeat-containing protein 5 (WDR5), a protein having WD-40 repeats, in order to connect MYC to chromatin and control the expression of genes involved in protein synthesis [34, 35]. Mutational analyses have revealed that mutations in MBI and MBII significantly impair MYC amplification, whereas mutations in MBIII enhance it. These data indicate that each MB domain interacts with distinct protein partners, affecting chromatin remodeling and transcription throughout the transcriptional cycle [36].

The structure of MYC is fundamental for its function as a transcriptional regulator and for the precise control of numerous cellular processes. In fact, MYC promotes the entry of cells into the S phase, regulating the cell cycle and activating genes, such as cyclin D, cyclin E, and cyclin-dependent kinase-4 (CDK4), essential for cell cycle progression, and simultaneously repressing cell cycle inhibitors, such as p21 and p27, ensuring continued proliferation [37, 38]. Furthermore, MYC modulates cellular metabolism to support the high energetic and biosynthetic demands of proliferation. It activates glycolysis enzymes, glutamine metabolism, and lipid and nucleotide biosynthesis, adapting the metabolism of tumor cells to the so-called Warburg effect [39]. MYC, under normal conditions, maintains cellular homeostasis, coordinating cell survival through the activation of proliferative pathways and promoting apoptosis after significant stresses, such as irreparable DNA damage [8]. Indeed, it can induce the activation of pro-apoptotic genes such as BAX and PUMA, while repressing anti-apoptotic genes such as BCL-2. However, in tumors, its regulation is subverted [5, 8, 40]. MYC overexpression, and in particular its hyperactivity, alters the correct balance between proliferation and apoptosis by enhancing growth signals and reducing sensitivity to programmed cell death signals [41, 42]. This “oncogenic addiction” makes MYC a crucial therapeutic target for the development of selective drugs.

3. MYC regulation between cell death and survival

Cell death is the irreversible arrest of cellular activity and an important physiological process in all organisms. It plays a crucial role in embryonic development, organ maintenance, and immune regulation [43]. In recent years, a greater understanding of the mechanism of programmed cell death or apoptosis has been gained and some key genes in this process have been identified such as MYC [44], which has a crucial role in the regulation of cell death through its ability to influence various pro-apoptotic pathways (BAX, PUMA, and NOXA (phorbol-12-myristate-13-acetate-induced protein 1) and anti-apoptotic pathways (BCL-2) [8, 45]. MYC regulates apoptosis through intrinsic and extrinsic death regulators: in particular, it stimulates the transcription of the intrinsic regulator BAX, which accumulates on the outer mitochondrial membrane facilitating its permeabilization [8, 46, 47]. This event triggers the movement of cytochrome c into the cytoplasm, promoting the formation of the apoptosome and subsequently the activation of caspases, triggering a cascade of events that culminate in DNA fragmentation and cell death [48, 49, 50]. MYC also has an involvement in the expression of two intrinsic targets: PUMA and NOXA, which neutralize anti-apoptotic proteins such as BCL-2 and B-cell lymphoma-extra large (BCL-XL), amplifying the apoptotic effect [51]. This function is enhanced by the ability of MYC to cooperate with p53, stabilizing and enhancing its transcriptional activity [52]. However, this balance can be disrupted in tumors, in which p53 is mutated or inactive, reducing the effectiveness of MYC-mediated apoptosis and promoting the survival of malignant cells [53, 54]. MYC also regulates the suppression of BCL-2, which plays a key role in protecting mitochondria from permeabilization. MYC-mediated suppression of BCL-2 controls the balance between pro- and anti-apoptotic factors, inducing programmed cell death in the absence of survival signals [55, 56]. In tumors, this balance is dysregulated, with an increase in the persistence of tumor cells and a reduction in their responsiveness to apoptotic stimuli [57]. Despite the complex dual role of MYC in cell growth and cell survival, in response to tumor microenvironment stimuli, the activation or inactivation of certain genes involved in these processes, aberrant MYC expression often exerts a dominant effect by suppressing apoptosis allowing cells to survive and proliferate in an uncontrolled manner (Figure 3) [58, 59, 60]. The paradoxical aspect of MYC biology is fully manifested in the concept of oncogene addiction, where tumor cells exploit its hyperactivity to sustain uncontrolled growth. Recent studies have reported the impact of MYC on several survival pathways, including the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway [61]. MYC, by positively regulating AKT signaling, indirectly promotes cell survival and inhibits apoptotic processes. In addition, AKT activation leads to the phosphorylation and inhibition of pro-apoptotic proteins, such as BCL-2-associated agonist of cell death (BAD), preventing cell death [62]. It has been reported that MYC enhances the anti-apoptotic gene expression, such as BCL-2 and BCL-XL. These proteins block the mitochondrial outer membrane permeabilization (MOMP), a critical step in the intrinsic apoptotic pathway [63]. By inhibiting MOMP, MYC effectively prevents the release of cytochrome c and the activation of caspases, which are key components of apoptosis [64]. MYC can suppress the pro-apoptotic genes’ transcription, such as BAX, thus preventing apoptosis and promoting cell proliferation, even under stress conditions [65]. Dysregulation of MYC can affect the appropriate function of p53, which has an essential function in the apoptotic process. MYC-driven cells often find mechanisms to inactivate or bypass p53 signaling [66, 67]. For example, MYC can increase the levels of murine double minute (MDM2), a negative regulator of p53, leading to a decrease in p53-mediated apoptosis. This is essential to allow MYC-overexpressing cells to proliferate, despite DNA damage or other stressors that would normally activate p53 [68]. Dysregulation of MYC then leads to rapid cellular proliferation, which can overwhelm normal DNA repair mechanisms and increase genomic instability, leading to the accumulation of mutations that can further inhibit apoptosis pathways, strengthening the pro-survival role of MYC [69].

4. Role of MYC in regulating apoptosis

MYC plays a crucial role in the control of multiple cellular processes, including proliferation, metabolism, and programmed cell death [70]. Although, MYC is primarily known for its ability to promote cell growth and proliferation, it also acts as a potent sensitizer of apoptotic signals [71]. This dual role of MYC is particularly relevant in the context of cancer, where the balance between proliferation and apoptosis determines the fate of transformed cells [72]. MYC is able to regulate both the intrinsic (mitochondrial) and extrinsic (death receptor-mediated) pathways of apoptosis [73]. The intrinsic pathway is characterized by the permeabilization of the mitochondrial membrane and the release of cytochrome c into the cytoplasm, an event that activates a caspase cascade, culminating in the degradation of cellular components [74]. MYC stimulates the expression of pro-apoptotic genes, such as BAX, BID, and PUMA, which promote the opening of mitochondrial pores and the release of cytochrome c, activating caspase-9 and, subsequently, executioner caspases such as caspase-3 and caspase-7 [75]. However, in tumor cells, this pro-apoptotic activity of MYC is often counteracted by the upregulation of anti-apoptotic proteins, such as BCL-2 and BCL-XL, which stabilize the mitochondrial membrane and prevent the initiation of the apoptotic cascade [76, 77]. In tumor contexts, MYC hyperactivity is associated with increased replicative stress and the production of reactive oxygen species (ROS), which can cause DNA damage and activate apoptosis [78]. However, mutations in tumor suppressor genes, such as p53, allow tumor cells to survive, despite high levels of stress. Indeed, p53 mutations, frequently observed in tumors, impair the ability of cells to respond to cellular damage by apoptosis [79, 80]. MYC modulates the balance between pro- and anti-apoptotic members of the BCL-2 family, both in a p53-dependent and -independent manner. Studies in Eμ-MYC transgenic mouse models of lymphoma have shown that MYC can regulate the expression of proteins such as BCL-2 and BCL-XL. In more than half of murine lymphomas, the levels of these anti-apoptotic proteins are elevated, even in the absence of functional p53, suggesting a p53-independent mechanism [76]. At the same time, MYC is able to indirectly suppress BCL-XL expression by reducing its RNA and protein levels. Such repression requires a new protein synthesis, suggesting an indirect transcriptional regulatory mechanism [77]. In parallel, MYC stimulates the expression of pro-apoptotic members such as BAX and BAK, which are essential for the activation of the mitochondrial apoptotic pathway. Indeed, MYC overexpression is associated with an increase in BAX expression at the transcriptional level, enhancing its functional activation [81]. The extrinsic apoptosis pathway is activated by the interaction between death receptors, such as FAS and TRAIL receptor (TRAIL-R, tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor), and their respective ligands. MYC is known to sensitize cells to these apoptotic signals by stimulating the expression of death receptors [82]. Activation of receptors such as FAS leads to the formation of the Death-Inducing Signaling Complex (DISC) and activation of caspase-8, which can act directly on executioner caspases or interact with the intrinsic pathway through the cleavage of BH3 interacting-domain death agonist (BID), an activator of mitochondrial permeabilization [83]. However, in tumors, the extrinsic apoptosis pathway is often deactivated by mechanisms that reduce the expression of death receptors or increase the levels of inhibitors, such as cellular FLICE-like inhibitory protein (c-FLIP), which block caspase-8 activation [84]. Furthermore, MYC counteracts survival signals associated with the death receptor pathway, such as activation of NF-κB, a known pro-survival factor [85]. Understanding the role of MYC in regulating apoptosis has important implications for the development of anticancer therapies. Drugs targeting anti-apoptotic proteins, such as venetoclax, a BCL-2 inhibitor, can reactivate the mitochondrial apoptotic cascade in tumor cells with overactive MYC, especially in hematological malignancies [86]. Similarly, restoring p53 function by compounds such as nutlin-3 could potentiate MYC-induced apoptosis [87]. Another promising strategy is the activation of the extrinsic apoptosis pathway by TRAIL ligands or agonist antibodies against death receptors [88]. These approaches exploit the predisposition of tumor cells with overactive MYC to succumb to apoptotic signals, offering therapeutic opportunities to treat aggressive tumors that are resistant to conventional therapies.

5. MYC in tumor progression

Cancer is a multifaceted process that needs the occurrence of multiple genetic alterations and the acquisition of distinct biological characteristics [89]. Notably, MYC activation is involved in multiple genetic deregulation and in the development of specific biological characteristics, such as proliferation, cell survival, metabolic alterations, angiogenesis, metastasis, and relapse [90]. Early in vitro investigations of MYC demonstrated its transformative potential when combined with other oncogenes in embryonic fibroblasts [91]. These findings demonstrated the ability of MYC to independently induce tumors in multiple tissues, while revealing its dependence on additional genetic alterations for complete tumorigenic activity in vivo [92]. For example, breast cancer induced by the transgenic expression of MYC developed K-Ras mutations, resulting in more aggressive tumors [93]. Similarly, induction of MYC in normal cells activates checkpoints such as Arf or p53, resulting in cell cycle arrest or apoptosis. In MYC-induced transgenic lymphomas, however, the proper functioning of Arf and p53 is subverted [94]. MYC controls the expression of different genes that influence cell growth, survival, and metabolism and directly impact tumor biology and the tumor microenvironment [95]. The role of MYC extends to modulating immune responses and other extrinsic factors that shape cancer progression [25]. Initially, MYC members were thought to play a universal role in human cancers, both hematological and solid, with L-MYC thought to be linked only to small cell lung cancer and N-MYC to neuroblastoma [96]. However, N-MYC and L-MYC seem to be involved in the occurrence of other cancers [97]. Thus, when examining the entire MYC family, it is clear that genetic activation of at least one of its members is a recurrent event in the majority of human cancers [5]. Dysregulation of MYC and related pathways is among the most widespread in human cancers. MYC hyperactivation in cancer occurs through epigenetic, genomic, and post-translational mechanisms, including amplifications, translocations, and upstream regulatory changes of its gene [98]. A pan-cancer analysis of 33 different human cancers, as reported in The Cancer Genome Atlas dataset, found that in 28% of tumors all members of the MYC family are amplified (Figure 4) [99]. These amplifications can cause MYC overexpression, either directly or indirectly, by activating genes involved in the MYC pathway [100]. MYC undergoes genetic amplification in several solid tumors, such as breast and liver cancers, and is often implicated in chromosomal translocations observed in B-cell and T-cell leukemias and lymphomas [101]. Retroviruses can enhance MYC expression through various mechanisms, including the insertion of enhancers upstream of the MYC gene and the activation of several oncogenic pathways such as SRC and Notch or loss of tumor suppressors such as adenomatous polyposis coli (APC) and transforming growth factor-beta (TGF-β) [102]. A lot of post-translational modifications determine MYC protein stability [103]. In normal conditions, a fine balance of phosphorylation events and proteasomal degradation determines the short half-life of MYC [104]. In tumors characterized by MYC overexpression, there is a notable increase in phospho-serine 62 (P-S62-MYC) levels and a corresponding decrease in phospho-threonine 58 (P-T58-MYC) levels. These alterations contribute to enhanced MYC stability and activity [105]. Rat sarcoma virus (RAS)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling mitogenic pathway increases the levels of P-S62, destabilizing MYC. MYC T58-related mutations can cause constitutive phosphorylation of S62. Tumors can also decrease the expression of the serine/threonine protein phosphatase 2A (PP2A), that dephosphorylating P-S62 leads to an accumulated amount of MYC [106]. In addition, peptidyl-prolyl cis-trans isomerase, NIMA-interacting 1 (PIN1), a peptidyl-prolyl cis-trans isomerase (PPIase), can contribute to MYC regulation in several tumors, such as uterine cancer (18%), colon cancer (16%), and cervical cancer (13%), through deletion, mutation, or epigenetic changes. These events can enhance tumor growth by increasing MYC levels [107]. Although MYC plays a central role in tumorigenesis, its activation alone is typically insufficient to convert normal cells into malignant ones [108]. Apoptosis, senescence, or cell cycle arrest are physiological processes that frequently impair MYC carcinogenic function. MYC dysregulation can induce p53 activation [109], cyclin-dependent kinase inhibitor 2A (CDKN2A) upregulation [110], or BCL-2 modulation [111, 112]. An additionally protective mechanism against tumorigenesis is the shortening of telomeres during cell division cycles, which limits proliferation [113]. However, MYC can promote cellular immortality by stimulating telomerase activity, through the regulation of telomerase reverse transcriptase [114]. These multiple levels of MYC regulation and dysfunction underscore its critical role in driving cancer progression.

6. MYC, a therapeutic target

Targeting MYC has demonstrated the ability to induce tumor regression through both direct and indirect effects, but it remains a therapeutic challenge due to MYC’s disordered structure and lack of a specific binding site or defined enzymatic activity [115]. Decades of research have highlighted several strategies to inhibit MYC activity that are emerging in preclinical models and clinical research [116]. Direct strategies include silencing MYC gene expression, disrupting MYC protein synthesis, or promoting its degradation via the proteasome (Figure 5) [117]. The MYC/MAX interaction is critical for the oncogenic function of MYC, and many approaches target this interaction [118]. For example, small compounds, such as MYCi361 and MYCi975, disrupt the MYC-MAX interface and promote phosphorylation of MYC on threonine-58, promoting proteasomal degradation of MYC [119]. Another study reported that KI-MS2-008 stabilizes MAX-MAX homodimers, reducing the levels of MYC and its transcriptional targets and suppressing tumor growth [120]. ME47, a minimalist small hybrid protein (MHP), disrupts the interaction with MAX by suppressing the transcriptional activity of MYC. These results suggest that MHPs offer an alternative therapeutic targeting method for transcription factors involved in human diseases, including cancer [121]. EN4, on the other hand, binds to an intrinsically disordered region of MYC (cysteine 171), reduces the thermal stability of MYC and MAX, inhibits MYC transcriptional activity, and suppresses carcinogenesis [122]. Another promising approach is to decrease MYC biosynthesis or enhance its degradation. Inhibitors targeting the PI3K-AKT-mTOR (mammalian target of rapamycin) signaling pathway have been shown to reduce MYC translation and lower MYC levels in tumors in mouse models [123]. Additionally, Silvestrol, an inhibitor of the translation initiator eukaryotic initiation factor-4A (eIF4A), suppresses MYC translation and prevents tumor growth in colon cancer mouse models [124]. Furthermore, Aurora kinase inhibitors can promote degradation of MYC protein and specifically reduce its overexpression in tumor cells without altering physiological expression of MYC [125]. Recently, substantial advancements have been achieved in developing specific protein degraders or chimeras, designed to directly induce the proteolysis of MYC (proteolysis targeting chimeras (PROTACs)) [126]. These approaches utilize the ubiquitin-proteasome system to degrade MYC, using bifunctional molecules with two components: a ligand that specifically binds to MYC and a ligand that targets an E3 ubiquitin ligase, such as cereblon or von Hippel-Lindau (VHL) [127]. Another potential strategy to reduce MYC levels is to target the stability of its messenger RNA (mRNA). Antisense oligonucleotides (ASOs), such as MYC-ASO, have been shown to reduce tumor development and stimulate antitumor immune responses in mouse models [128]. Another approach is to suppress MYC transcription. Bromodomain and extra-terminal motif (BET) inhibitors, epigenetic regulators, including IZCZ-3, that stabilize the G-quadruplex structure in the MYC promoter region, have shown antitumor activity [129]. Indirect targeting strategies exploit synthetic lethal interactions, targeting vulnerabilities in MYC-driven cells (Figure 5). For example, inhibiting MYC transcriptional activity through genetic approaches, such as the use of OmoMYC, a dominant negative allele that competes with MYC/MAX for chromatin binding, reducing MYC/MAX occupancy at its targets and modulating gene expression in tumors with high MYC oncogenic activity [130]. Epigenetic modifiers, such as histone deacetylase inhibitor (HDACi) and histone methyltransferase (Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2)) inhibitors, have been used to treat MYC-induced malignancies. The combination of HDACi and EZH2 reduced MYC levels and activated immune transcriptional pathways, enhancing T-cell-mediated antitumor responses through C-C motif chemokine ligand 5 (CCL5) expression [131, 132]. Recent studies have shown that the use of epigenetic treatments can reduce MYC, reversing immune evasion. Similarly, MYC can cause cancer by regulating chromatin remodeling via miR17-92. Anti-miR-17 oligonucleotides inhibited tumor progression in a liver cancer mouse model [133]. Research continues to develop innovative approaches to target MYC, exploiting both its molecular dependencies and interactions with the immune system. These advances offer new perspectives for the treatment of MYC-induced malignancies.

7. Emerging strategies for targeting MYC in cancer therapy

Targeting MYC in cancer therapy is a promising but challenging frontier due to its critical role in cellular processes and its classification as a “difficult-to-drug” molecule [134]. Future directions to overcome these challenges and exploit MYC as a therapeutic target include several innovative approaches [135]. Studies are underway to design small molecules that disrupt MYC-MAX dimerization, which is essential for MYC transcriptional activity [136]. Additionally, PROTACs are being explored to selectively degrade MYC protein by exploiting the ubiquitin-proteasome system [137]. Clinical trials of OmoMYV a MYC inhibitory peptide, are expanding, along with investigations of its derivatives and other direct MYC inhibitors [138]. Tumors that overexpress MYC have specific vulnerabilities, such as dependence on cyclin-dependent kinases (CDKs), DNA repair enzymes (checkpoint kinase 1 (CHK1), ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR)), and anti-apoptotic proteins such as myeloid cell leukemia 1 (MCL1). Combining MYC inhibition with drugs that target these synthetic lethal pathways promises to improve therapeutic efficacy and mitigate resistance [5, 139]. HDACi are being explored to regulate MYC-driven transcriptional programs [140, 141]. Similarly, BET inhibitors, which block MYC transcription by interfering with chromatin regulators, offer another promising avenue for treatment [142]. Techniques such as antisense RNA are being developed to directly silence overexpressed MYC mRNA [143]. In addition, MYC inhibition is being combined with immune checkpoint inhibitors to exploit MYC’s role in immune evasion [144]. These multifaceted approaches, individually and in combination, aim to address the complexity of MYC targeting and offer hope for more effective and personalized cancer therapies in the future.

8. Conclusions

MYC plays a pivotal and multifaceted role in tumorigenesis and cancer progression, regulating numerous cellular processes, such as the cell cycle, metabolism, and transcription [145]. It functions as a key determinant of the balance between cell survival and cell death through its transcriptional regulation of a wide range of genes [146]. This dual role makes MYC a critical factor in carcinogenesis. When functioning correctly, MYC can drive cells toward apoptosis, acting as a safeguard against uncontrolled proliferation [147]. However, dysregulation of MYC, often resulting from mutations or concurrent alterations in other oncogenes or tumor suppressor genes, can circumvent apoptosis and promote unchecked cell growth [148].

Despite its critical involvement in cancer, targeting MYC directly poses significant challenges. Its lack of enzymatic pockets and its pervasive overexpression in tumors make it a difficult therapeutic target [108]. Nevertheless, substantial progress has been made in developing strategies to inhibit MYC activity. However, clinical treatments that effectively target MYC remain elusive [149]. An understanding of the mechanisms by which MYC governs tumorigenesis versus apoptosis is essential [103]. Such insights could refine therapeutic approaches, enabling the precise targeting of MYC in cancer cells while minimizing adverse effects.

Acknowledgments

This study was supported by PRIN2022, PNRR P2022CKMPW project, PRIN2020 2020CW39SJ project, and PNRR-MAD-2022-12376672.

Conflict of interest

The authors declare no conflict of interest.

Acronyms and abbreviations