Pathogenesis and therapeutic targeting of aberrant <scp>MYC</scp> expression in haematological cancers

Schick, Markus; Habringer, Stefan; Nilsson, Jonas A.; Keller, Ulrich

doi:10.1111/bjh.14917

Cited by 37 publications

(30 citation statements)

References 162 publications

(185 reference statements)

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“…An increase in MYC expression has been associated with increased cancer cell proliferation and survival due to its pleiotropic effects on cell signalling pathways. For example, MYC can activate IRF4, MCL1, and Cyclin D1 expression, regulating cell death and cell cycle pathways [ 42 , 43 ]. Importantly, MYC was described as an important target of bromodomain proteins, including BRD4, and inhibition of bromodomain proteins by JQ1 leads to a significant decrease in MYC expression [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Predicting response to BET inhibitors using computational modeling: A BEAT AML project study

et al. 2019

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Despite advances in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), overall survival rates remain low. The ability to predict treatment response based on individual cancer genomics using computational modeling will aid in the development of novel therapeutics and personalize care. Here, we used a combination of genomics, computational biology modeling (CBM), ex vivo chemosensitivity assay, and clinical data from 100 randomly selected patients in the Beat AML project to characterize AML sensitivity to a bromodomain (BRD) and extra-terminal (BET) inhibitor. Computational biology modeling was used to generate patient-specific protein network maps of activated and inactivated protein pathways translated from each genomic profile. Digital drug simulations of a BET inhibitor (JQ1) were conducted by quantitatively measuring drug effect using a composite AML disease inhibition score. 93% of predicted disease inhibition scores matched the associated ex vivo IC 50 value. Sensitivity and specificity of CBM predictions were 97.67%, and 64.29%, respectively. Genomic predictors of response were identified. Patient samples harbouring chromosomal aberrations del(7q) or −7, +8, or del(5q) and somatic mutations causing ERK pathway dysregulation, responded to JQ1 in both in silico and ex vivo assays. This study shows how a combination of genomics, computational modeling and chemosensitivity testing can identify network signatures associating with treatment response and can inform priority populations for future clinical trials of BET inhibitors.

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Section: Discussionmentioning

confidence: 99%

Predicting response to BET inhibitors using computational modeling: A BEAT AML project study

et al. 2019

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“… 42 MYC is a major cell regulator in many processes including cell cycle entry, ribosome biogenesis, and metabolism. 43 , 44 Deregulation of MYC associated with tumor aggressiveness, metastatic potential, therapeutic resistance, and poor patient outcome has been reported in various cancers. 43 , 44 MYCL was reported to correlate with the progression of small cell lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“… 43 , 44 Deregulation of MYC associated with tumor aggressiveness, metastatic potential, therapeutic resistance, and poor patient outcome has been reported in various cancers. 43 , 44 MYCL was reported to correlate with the progression of small cell lung cancer. 45 With the exception of increased MYC expression, these data support our migration assay results; however, further examination will be required to clarify the exact functional mechanism of Cav-1 in the progression of PC.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 and -2 regulate cell motility in castration-resistant prostate cancer

Kamibeppu

Yamasaki

Nakahara

et al. 2018

RRU

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BackgroundCaveolin (Cav)-1 and Cav-2 are cell membrane proteins, which are structural proteins of caveolae and are reported to be positive regulators of cell survival and metastasis in prostate cancer (PC). In a previous study, we reported that elevated levels of Cav-1 and Cav-2 were significantly associated with PC progression. However, their functions in PC have not yet been clarified. In this study, we examined the function of Cav-1 and Cav-2 in PC cell invasiveness and motility.Materials and methodsWe introduced Cav-1- and Cav-2-specific small interfering into PC3 cells to knock-down (KD) both molecules. We also performed cell proliferation assay, wound healing assay, migration assay, and invasion assay using PC3 cells and compared the results between Cav-1-KD, Cav-2-KD, and negative control PC3 cells. In addition, we performed real-time quantitative PCR (RT-qPCR) and RT2 Profiler PCR Array analysis to identify factors influencing migration.ResultsWe observed no significant difference in the proliferative and invasive activities of Cav-1-KD and Cav-2-KD PC3 cells; however, the cell motility was significantly decreased compared with negative control PC3 cells. RT-qPCR revealed that the expression of vimentin and N-cadherin was downregulated in Cav-1-KD PC3 cells. In addition, PCR array revealed a decreased expression of MGAT5, MMP13, and MYCL in Cav-1-KD PC3 and ETV4, FGFR4, and SRC in Cav-2-KD PC3.ConclusionCav-1 and Cav-2 may positively contribute to the upregulation of castration-resistant PC cell migration. Cav-induced regulation of several molecules including vimentin, N-cadherin, MGAT5, MMP13, MYCL, ETV4, FGFR4, and SRC may have an important role in PC3 cell motility. However, further examination will be required.

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“…6,7,12,13 Overexpression of the intrinsically disordered oncoprotein, c-MYC, is found more than 50% of all human cancer, with high prevalence in cancers of hematopoietic origin, such as acute lymphoblastic leukemia and multiple myeloma. 14 In normal cells, c-MYC protein levels are kept in check through multiple posttranslational modifications that alter susceptibility toward proteasomal degradation by default. 15 Dysregulation of c-MYC clearance can induce its oncogenic transcriptional activity, resulting in the transcription of multiple tumor promoting genes.…”

Section: Introductionmentioning

confidence: 99%

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

Njomen

Lansdell

Vanecek

et al. 2020

Preprint

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Enhancing proteasome activity is a potential new therapeutic strategy to prevent the accumulation of aberrant high levels of protein that drive the pathogenesis of many diseases. Herein, we examine the use of small mole-cules to activate the 20S proteasome to reduce aberrant signaling by the undruggable oncoprotein c-MYC, to treat c-MYC driven oncogenesis. Overexpression of c-MYC is found in more than 50% of all human cancer but remains undruggable because of its highly dynamic intrinsically disordered 3-D conformation, which renders traditional therapeutic strategies largely ineffective. We demonstrate herein that small molecule activation of the 20S proteasome targets dysregulated intrinsically disordered proteins (IDPs), including c-MYC, and reduces can-cer growth in vitro and in vivo models of multiple myeloma, and is even effective in bortezomib resistant cells and unresponsive patient samples. Genomic analysis of various cancer pathways showed that proteasome activation results in downregulation of many c-MYC target genes. Moreover, proteasome enhancement was well tolerated in mice and dogs. These data support the therapeutic potential of 20S proteasome activation in tar-geting IDP-driven proteotoxic disorders, including cancer, and demonstrate that this new therapeutic strategy is well tolerated in vivo.

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Pathogenesis and therapeutic targeting of aberrant MYC expression in haematological cancers

Cited by 37 publications

References 162 publications

Predicting response to BET inhibitors using computational modeling: A BEAT AML project study

Predicting response to BET inhibitors using computational modeling: A BEAT AML project study

Caveolin-1 and -2 regulate cell motility in castration-resistant prostate cancer

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

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