MYC inhibitors in multiple myeloma

Martínez-Martín, Sandra; Soucek, Laura

doi:10.20517/cdr.2021.55

Cited by 11 publications

(11 citation statements)

References 149 publications

(284 reference statements)

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“…On the one hand, oncogenes such as CMYC, KRAS, and mutant p53 affect alternative splicing; on the other hand, their activity can be increased by this process. Many reviews discussed how the selected oncogene affects the hallmarks of cancer: CMYC [238], KRAS [44], mutant p53 [54], SRPK1 [9]. Here we emphasized that none of these oncogenic proteins and pathways works alone, but, rather, cooperate to contribute to hallmarks of cancer.…”

Section: Discussionmentioning

confidence: 92%

How Driver Oncogenes Shape and Are Shaped by Alternative Splicing Mechanisms in Tumors

Wojtyś,

Oroń

2023

Cancers

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The development of RNA sequencing methods has allowed us to study and better understand the landscape of aberrant pre-mRNA splicing in tumors. Altered splicing patterns are observed in many different tumors and affect all hallmarks of cancer: growth signal independence, avoidance of apoptosis, unlimited proliferation, invasiveness, angiogenesis, and metabolism. In this review, we focus on the interplay between driver oncogenes and alternative splicing in cancer. On one hand, oncogenic proteins—mutant p53, CMYC, KRAS, or PI3K—modify the alternative splicing landscape by regulating expression, phosphorylation, and interaction of splicing factors with spliceosome components. Some splicing factors—SRSF1 and hnRNPA1—are also driver oncogenes. At the same time, aberrant splicing activates key oncogenes and oncogenic pathways: p53 oncogenic isoforms, the RAS-RAF-MAPK pathway, the PI3K-mTOR pathway, the EGF and FGF receptor families, and SRSF1 splicing factor. The ultimate goal of cancer research is a better diagnosis and treatment of cancer patients. In the final part of this review, we discuss present therapeutic opportunities and possible directions of further studies aiming to design therapies targeting alternative splicing mechanisms in the context of driver oncogenes.

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Section: Discussionmentioning

confidence: 92%

How Driver Oncogenes Shape and Are Shaped by Alternative Splicing Mechanisms in Tumors

Wojtyś,

Oroń

2023

Cancers

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“…Success in this arena has also had to contend with the disordered nature of MYC, which by the physical standards of the time, vide supra , made it a quite complex and challenging drug target to model . Further confidence in the modulation of MYC also waned because the MYC-MAX heterodimer has an estimated protein-protein interaction (PPI) surface area of over 3000 Å and, as well-documented, PPIs lack well-defined pockets or grooves that could be used for high-energy binding interactions with a small ligand. , …”

Section: Discussionmentioning

confidence: 99%

“…114 Further confidence in the modulation of MYC also waned because the MYC-MAX heterodimer has an estimated protein-protein interaction (PPI) surface area of over 3000 Å 115 and, as well-documented, PPIs lack well-defined pockets or grooves that could be used for high-energy binding interactions with a small ligand. 68,116 At the clinical level, therapeutic efforts against MYC and MYC-MAX have also stalled due to off-target effects on other oncoproteins. 117 While more efforts on oncogene selectivity are warranted, new MYC drug candidates will also need to contend with fast metabolism, nonselective distribution after systematic dosing, and tumor penetrability of these small molecule and peptide inhibitors, all of which will undoubtably hold back their clinical feasibility.…”

Section: ■ Outlookmentioning

confidence: 99%

Demystifying the Druggability of the MYC Family of Oncogenes

et al. 2023

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The MYC family of oncogenes (MYC, MYCN, and MYCL) encodes a basic helix−loop−helix leucine zipper (bHLHLZ) transcriptional regulator that is responsible for moving the cell through the restriction point. Through the HLHZIP domain, MYC heterodimerizes with the bHLHLZ protein MAX, which enables this MYC-MAX complex to bind to E-box regulatory DNA elements thereby controlling transcription of a large group of genes and their proteins. Translationally, MYC is one of the foremost oncogenic targets, and deregulation of expression of the MYC family gene/proteins occurs in over half of all human tumors and is recognized as a hallmark of cancer initiation and maintenance. Additionally, unexpected roles for this oncoprotein have been found in cancers that nominally have a non-MYC etiology. Although MYC is rarely mutated, its gain of function in cancer results from overexpression or from amplification. Moreover, MYC is a pleiotropic transcription factor possessing broad pathogenic prominence making it a coveted cancer target. A widely held notion within the biomedical research community is that the reliable modulation of MYC represents a tremendous therapeutic opportunity given its role in directly potentiating oncogenesis. However, the MYC-MAX heterodimer interaction contains a large surface area with a lack of well-defined binding sites creating the perception that targeting of MYC-MAX is forbidding. Here, we discuss the biochemistry behind MYC and MYC-MAX as it relates to cancer progression associated with these transcription factors. We also discuss the notion that MYC should no longer be regarded as undruggable, providing examples that a therapeutic window is achievable despite global MYC inhibition.

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“…Other AKT inhibitors include the following compounds: Afuresertib (GSK2110183), Uprosertib (GSK2141795, GSK795) and Ordidonin (NSC-250682) [16]. Additionally, various drug candidates are in development with MYC pathway inhibition profiles [17]:…”

Section: Current Treatment Options and Experimental Drug Candidatesmentioning

confidence: 99%

A Systems Biology Analysis of Chronic Lymphocytic Leukemia

Pozzati,

Zhou,

Hazan

et al. 2024

Preprint

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Whole-genome sequencing has revealed that TP53, NOTCH1, ATM, SF3B1, BIRC3, ABL, NXF1, BCR, ZAP70 are often mutated in CLL, but not consistently across all CLL patients. This paper employs a statistical thermodynamics approach in combination with the systems biology of the CLL protein-protein interaction networks to identify the most significant participant proteins in the cancerous transformation. Betti number (a topology of complexity) estimates highlight a protein hierarchy, primarily in the Wnt pathway known for aberrant CLL activation. These individually identified proteins suggest a network-targeted strategy over single-target drug development. The findings advocate for a multi-target inhibition approach, limited to several key proteins to minimize side effects, thereby providing a foundation for designing therapies. This study emphasizes a shift towards a comprehensive, multi-scale analysis to enhance personalized treatment strategies for CLL, which could be experimentally validated using siRNA or small molecule inhibitors. The result is not just the identification of these proteins but their rank-order, offering a potent signal amplification in the context of the 20,000 proteins produced by the human body, thus providing a strategic basis for therapeutic intervention in CLL, underscoring the necessity for a more holistic, cellular, chromosomal, and genome-wide study to develop tailored treatments for CLL patients.

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MYC inhibitors in multiple myeloma

Cited by 11 publications

References 149 publications

How Driver Oncogenes Shape and Are Shaped by Alternative Splicing Mechanisms in Tumors

How Driver Oncogenes Shape and Are Shaped by Alternative Splicing Mechanisms in Tumors

Demystifying the Druggability of the MYC Family of Oncogenes

A Systems Biology Analysis of Chronic Lymphocytic Leukemia

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