Targeting "undruggable" c-Myc protein by synthetic lethality

doi:10.1007/s11684-020-0780-y

Review

. 2021 Aug;15(4):541-550.

doi: 10.1007/s11684-020-0780-y. Epub 2021 Mar 4.

Targeting "undruggable" c-Myc protein by synthetic lethality

Chen Wang^{1

2

3}, Hui Fang², Jiawei Zhang⁴, Ying Gu^{5

6

7}

Affiliations

¹ Division of Genome Medicine and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
² Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, China.
³ Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 311121, China.
⁴ Division of Genome Medicine and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. jwzhang@zju.edu.cn.
⁵ Division of Genome Medicine and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. guyinghz@zju.edu.cn.
⁶ Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, China. guyinghz@zju.edu.cn.
⁷ Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 311121, China. guyinghz@zju.edu.cn.

PMID: 33660217
DOI: 10.1007/s11684-020-0780-y

Review

Targeting "undruggable" c-Myc protein by synthetic lethality

Chen Wang et al. Front Med. 2021 Aug.

. 2021 Aug;15(4):541-550.

doi: 10.1007/s11684-020-0780-y. Epub 2021 Mar 4.

Authors

Chen Wang^{1

2

3}, Hui Fang², Jiawei Zhang⁴, Ying Gu^{5

6

7}

Affiliations

¹ Division of Genome Medicine and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
² Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, China.
³ Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 311121, China.
⁴ Division of Genome Medicine and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. jwzhang@zju.edu.cn.
⁵ Division of Genome Medicine and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. guyinghz@zju.edu.cn.
⁶ Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, China. guyinghz@zju.edu.cn.
⁷ Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 311121, China. guyinghz@zju.edu.cn.

PMID: 33660217
DOI: 10.1007/s11684-020-0780-y

Abstract

Synthetic lethal screening, which exploits the combination of mutations that result in cell death, is a promising method for identifying novel drug targets. This method provides a new avenue for targeting "undruggable" proteins, such as c-Myc. Here, we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network, whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells. We further discuss strategies to identify these functional nodes in the context of synthetic lethality. We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.

Keywords: c-Myc; synthetic lethality; transcription factor; undruggable.

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References

1. Pan J, Deng Q, Jiang C, Wang X, Niu T, Li H, Chen T, Jin J, Pan W, Cai X, Yang X, Lu M, Xiao J, Wang P. USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene 2015; 34(30): 3957–3967 - PubMed
1. Sun XX, He X, Yin L, Komada M, Sears RC, Dai MS. The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Proc Natl Acad Sci USA 2015; 112(12): 3734–3739 - PubMed - PMC
1. Whitfield JR, Beaulieu ME, Soucek L. Strategies to inhibit Myc and their clinical applicability. Front Cell Dev Biol 2017; 5: 10 - PubMed - PMC
1. Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, Galloway DA, Gu W, Gautier J, Dalla-Favera R. Non-transcriptional control of DNA replication by c-Myc. Nature 2007; 448(7152): 445–451 - PubMed
1. Wilson A, Murphy MJ, Oskarsson T, Kaloulis K, Bettess MD, Oser GM, Pasche AC, Knabenhans C, Macdonald HR, Trumpp A. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 2004; 18(22): 2747–2763 - PubMed - PMC

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[1] Pan J, Deng Q, Jiang C, Wang X, Niu T, Li H, Chen T, Jin J, Pan W, Cai X, Yang X, Lu M, Xiao J, Wang P. USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene 2015; 34(30): 3957–3967 - PubMed

[2] Pan J, Deng Q, Jiang C, Wang X, Niu T, Li H, Chen T, Jin J, Pan W, Cai X, Yang X, Lu M, Xiao J, Wang P. USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene 2015; 34(30): 3957–3967 - PubMed

[3] Sun XX, He X, Yin L, Komada M, Sears RC, Dai MS. The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Proc Natl Acad Sci USA 2015; 112(12): 3734–3739 - PubMed - PMC

[4] Sun XX, He X, Yin L, Komada M, Sears RC, Dai MS. The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Proc Natl Acad Sci USA 2015; 112(12): 3734–3739 - PubMed - PMC

[5] Whitfield JR, Beaulieu ME, Soucek L. Strategies to inhibit Myc and their clinical applicability. Front Cell Dev Biol 2017; 5: 10 - PubMed - PMC

[6] Whitfield JR, Beaulieu ME, Soucek L. Strategies to inhibit Myc and their clinical applicability. Front Cell Dev Biol 2017; 5: 10 - PubMed - PMC

[7] Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, Galloway DA, Gu W, Gautier J, Dalla-Favera R. Non-transcriptional control of DNA replication by c-Myc. Nature 2007; 448(7152): 445–451 - PubMed

[8] Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, Galloway DA, Gu W, Gautier J, Dalla-Favera R. Non-transcriptional control of DNA replication by c-Myc. Nature 2007; 448(7152): 445–451 - PubMed

[9] Wilson A, Murphy MJ, Oskarsson T, Kaloulis K, Bettess MD, Oser GM, Pasche AC, Knabenhans C, Macdonald HR, Trumpp A. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 2004; 18(22): 2747–2763 - PubMed - PMC

[10] Wilson A, Murphy MJ, Oskarsson T, Kaloulis K, Bettess MD, Oser GM, Pasche AC, Knabenhans C, Macdonald HR, Trumpp A. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 2004; 18(22): 2747–2763 - PubMed - PMC

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Targeting "undruggable" c-Myc protein by synthetic lethality

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Targeting "undruggable" c-Myc protein by synthetic lethality

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