Capitalizing on Synthetic Lethality of MYC to Treat Cancer in the Digital Age
Authors: Dexter Kai Hao Thng, Tan Boon Toh, Edward Kai-Hua Chow
Journal: Trends in Pharmacological Sciences (2021)

Synthetic lethality can be capitalised on to indirectly target the undruggable MYC oncoprotein and impede tumourigenesis in MYC-driven tumours.Synthetic lethal targets of MYC include regulators of MYC expression, regulators of MYC turnover, and functional pathways downstream of MYC, such as cellular metabolism and proliferation.Development of inhibitors against synthetic lethal targets of MYC have successfully entered the clinical phase, albeit in the early stages with foreseeable challenges in the near future.In silico platforms can be used to streamline and automate the drug development pipeline by leveraging on publicly available databases and computational algorithms. Deregulation of MYC is among the most frequent oncogenic drivers of cancer. Developing targeted therapies against MYC is, therefore, one of the most critical unmet needs of cancer therapy. Unfortunately, MYC has been labelled as undruggable due to the lack of success in developing clinically relevant MYC-targeted therapies. Synthetic lethality is a promising approach that targets MYC-dependent vulnerabilities in cancer. However, translating the synthetic lethality targets to the clinics is still challenging due to the complex nature of cancers. This review highlights the most promising mechanisms of MYC synthetic lethality and how these discoveries are currently translated into the clinic. Finally, we discuss how in silico computational platforms can improve clinical success of synthetic lethality-based therapy. Deregulation of MYC is among the most frequent oncogenic drivers of cancer. Developing targeted therapies against MYC is, therefore, one of the most critical unmet needs of cancer therapy. Unfortunately, MYC has been labelled as undruggable due to the lack of success in developing clinically relevant MYC-targeted therapies. Synthetic lethality is a promising approach that targets MYC-dependent vulnerabilities in cancer. However, translating the synthetic lethality targets to the clinics is still challenging due to the complex nature of cancers. This review highlights the most promising mechanisms of MYC synthetic lethality and how these discoveries are currently translated into the clinic. Finally, we discuss how in silico computational platforms can improve clinical success of synthetic lethality-based therapy. Cancer is a genomic disease resulting from an accumulation of genetic lesions in the cell. Specific genetic lesions, such as oncogene activation of KRAS and MYC, have been identified as contributors to tumourigenesis. Driver mutations in tumours can be exploited for therapeutic strategies that specifically target these oncoproteins. Furthermore, with the advent of big data and machine learning, researchers now have access to much larger genomic datasets, facilitating the subtyping of different tumours according to their genomic profiles. This has paved the way for precision medicine, where treatment regiments for patients are tailored according to their genetic profile, which has improved targeted therapy response rates. Despite advances in targeted therapy, not all driver mutations in tumours are currently targetable. These undruggable targets include the oncogenes KRAS and MYC [1.Dang C.V. et al.Drugging the 'undruggable' cancer targets.Nat. Rev. Cancer. 2017; 17: 502-508Crossref PubMed Scopus (211) Google Scholar]. To circumvent the issue of undruggability, studies have turned to synthetic lethality as the next ideal treatment strategy for oncogene-addicted tumours. Through a diverse repertoire of techniques, researchers have successfully looked to identifying and exploiting novel vulnerabilities in these tumours as a strategy to target oncogene addiction indirectly [1.Dang C.V. et al.Drugging the 'undruggable' cancer targets.Nat. Rev. Cancer. 2017; 17: 502-508Crossref PubMed Scopus (211) Google Scholar]. Synthetic lethality initially described a state in which the loss of either of two genes is viable for the cell, but the simultaneous inactivation of both genes is lethal. Since synthetic lethality in cancer was first proposed over 20 years ago, numerous synthetic lethal gene pairs have been discovered [2.Hartwell L.H. et al.Integrating genetic approaches into the discovery of anticancer drugs.Science. 1997; 278: 1064-1068Crossref PubMed Scopus (517) Google Scholar]. Synthetic lethality has now been expanded to describe a general state where cancer cells develop specific vulnerabilities upon perturbations to the cellular system (which may not always be genetic in nature). Broadly, we can classify synthetic lethality into three categories – oncogene-addicted, non-oncogene-based, and drug-based synthetic lethality (Box 1), opening the door to novel strategies to target the undruggable. The most classic synthetic lethal gene pair in cancer therapy is the inhibition of poly (ADP-ribose) polymerase (PARP) in BRCA-deficient tumours. Two landmark papers have demonstrated that tumours harbouring BRCA1 and BRCA2 mutations were selectively more sensitive to PARP inhibition due to the failure to repair recombination lesions induced by PARP inhibitors [3.Bryant H.E. et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature. 2005; 434: 913-917Crossref PubMed Scopus (2917) Google Scholar,4.Farmer H. et al.Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature. 2005; 434: 917-921Crossref PubMed Scopus (3776) Google Scholar]. Since its discovery, PARP inhibitors have now been approved for the treatment of BRCA-mutated ovarian, breast, and pancreatic cancers, making it the first clinically applied synthetic lethality targeted therapy. This led to a growing interest in the development of synthetic lethality targeted therapies against various cancers.Box 1Examples of Synthetic Lethality in CancerThe first category of synthetic lethality are dependencies in tumours with an oncogene addiction (Figure IA). The abrogation of these dependencies is lethal for oncogene-addicted tumours. One common oncogene addiction in cancer is the dependency on KRAS, resulting in several vulnerabilities which can be exploited for treating KRAS-driven tumours [100.Aguirre A.J. Hahn W.C. Synthetic lethal vulnerabilities in KRAS-mutant cancers.Cold Spring Harb. Perspect. Med. 2018; 8Crossref PubMed Scopus (22) Google Scholar]. The second category of non-oncogene-based synthetic lethality is the loss or mutation of a single gene sensitises tumour cells to the inhibition of a complementary pathway (Figure IB). The most classic example is synthetic lethality between mutant BRCA genes and PARP inhibition as a result of enhanced DNA damage coupled with inefficient DNA repair [3.Bryant H.E. et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature. 2005; 434: 913-917Crossref PubMed Scopus (2917) Google Scholar,4.Farmer H. et al.Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature. 2005; 434: 917-921Crossref PubMed Scopus (3776) Google Scholar]. Finally, drug-based synthetic lethality can be observed in tumours resistant to monotherapies but sensitive to combination therapies due to compensatory pathways that sustain tumour growth (Figure IC). Simultaneous pharmacological inhibition of both pathways is therefore lethal for the cancer cell. For instance, the dual inhibition of both the EGFR and BRAF pathways in cancer cells harbouring the BRAFV600E mutation was shown to be synthetically lethal, overcoming resistance to BRAF inhibitor, vemurafenib [101.Notarangelo T. et al.Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells.Cancer Cell Int. 2017; 17: 86Crossref PubMed Scopus (11) Google Scholar]. The first category of synthetic lethality are dependencies in tumours with an oncogene addiction (Figure IA). The abrogation of these dependencies is lethal for oncogene-addicted tumours. One common oncogene addiction in cancer is the dependency on KRAS, resulting in several vulnerabilities which can be exploited for treating KRAS-driven tumours [100.Aguirre A.J. Hahn W.C. Synthetic lethal vulnerabilities in KRAS-mutant cancers.Cold Spring Harb. Perspect. Med. 2018; 8Crossref PubMed Scopus (22) Google Scholar]. The second category of non-oncogene-based synthetic lethality is the loss or mutation of a single gene sensitises tumour cells to the inhibition of a complementary pathway (Figure IB). The most classic example is synthetic lethality between mutant BRCA genes and PARP inhibition as a result of enhanced DNA damage coupled with inefficient DNA repair [3.Bryant H.E. et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature. 2005; 434: 913-917Crossref PubMed Scopus (2917) Google Scholar,4.Farmer H. et al.Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature. 2005; 434: 917-921Crossref PubMed Scopus (3776) Google Scholar]. Finally, drug-based synthetic lethality can be observed in tumours resistant to monotherapies but sensitive to combination therapies due to compensatory pathways that sustain tumour growth (Figure IC). Simultaneous pharmacological inhibition of both pathways is therefore lethal for the cancer cell. For instance, the dual inhibition of both the EGFR and BRAF pathways in cancer cells harbouring the BRAFV600E mutation was shown to be synthetically lethal, overcoming resistance to BRAF inhibitor, vemurafenib [101.Notarangelo T. et al.Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells.Cancer Cell Int. 2017; 17: 86Crossref PubMed Scopus (11) Google Scholar]. In this review, we describe how synthetic lethality can be harnessed for the treatment of tumours dependent on one of the most common oncogene drivers – MYC (henceforth referred to as MYC-driven/dependent tumours) [5.Schaub F.X. et al.Pan-cancer alterations of the MYC oncogene and its proximal network across the Cancer Genome Atlas.Cell Syst. 2018; 6: 282-300 e2Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar], with a focus on the identification of synthetic lethal targets of MYC. Additionally, we discuss the prospects and challenges of translating MYC synthetic lethality from preclinical studies to patients with MYC-dependent tumours. Finally, we explore the potential of in silico methodologies to identify and target synthetic lethality targets of MYC in the age of artificial intelligence and big data. MYC is a transcriptional regulator first identified as a viral oncogene in avian myelocytomatosis virus, functioning as a master regulator of cell growth [6.Vennstrom B. et al.Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29.J. Virol. 1982; 42: 773-779Crossref PubMed Google Scholar]. Two paralogs of MYC, MYCN and MYCL, are tissue-specific factors that generally perform similar functions and will henceforth be collectively referred to as MYC. Across the numerous cancer types, MYC has been reported to be deregulated, acting as a key oncogenic driver in the tumorigenesis process and hence potential therapeutic target (Box 2).Box 2Reversal of Tumourigenesis in MYC-Driven TumoursGiven the critical role of MYC as a cancer-driving oncogene, it is reasonable to conclude that MYC-addicted tumours benefit from abrogation of MYC function. In fact, several MYC-induced in vivo cancer models have demonstrated that the abrogation of MYC function was able to reverse the tumorigenesis process[94.Gabay M. et al.MYC activation is a hallmark of cancer initiation and maintenance.Cold Spring Harb. Perspect. Med. 2014; 4a014241Crossref PubMed Scopus (316) Google Scholar]. This has been observed across various haematological and solid cancers (Table I). The promise of MYC as a therapeutic target in MYC-driven cancers is therefore undeniable, prompting the development of potential MYC inhibitors.Table IDevelopment of MYC-Driven Mouse Cancer Models, Updated from Gabay et al. [94.Gabay M. et al.MYC activation is a hallmark of cancer initiation and maintenance.Cold Spring Harb. Perspect. Med. 2014; 4a014241Crossref PubMed Scopus (316) Google Scholar].Tumour typeMalignancyRefsHaematologicalT cell acute lymphoblastic leukaemia[102.Felsher D.W. Bishop J.M. Reversible tumorigenesis by MYC in hematopoietic lineages.Mol. Cell. 1999; 4: 199-207Abstract Full Text Full Text PDF PubMed Scopus (652) Google Scholar,103.Marinkovic D. et al.Reversible lymphomagenesis in conditionally c-MYC expressing mice.Int. J. Cancer. 2004; 110: 336-342Crossref PubMed Scopus (61) Google Scholar]B cell acute lymphoblastic leukaemia[103.Marinkovic D. et al.Reversible lymphomagenesis in conditionally c-MYC expressing mice.Int. J. Cancer. 2004; 110: 336-342Crossref PubMed Scopus (61) Google Scholar]Multiple myeloma[104.Chesi M. et al.AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies.Cancer Cell. 2008; 13: 167-180Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar]SolidBreast cancer[86.Lourenco C. et al.Modelling the MYC-driven normal-to-tumour switch in breast cancer.Dis. Model. Mech. 2019; 12Crossref PubMed Scopus (3) Google Scholar,105.D'Cruz C.M. et al.c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations.Nat. Med. 2001; 7: 235-239Crossref PubMed Scopus (0) Google Scholar]Liver cancers[106.Shachaf C.M. et al.MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.Nature. 2004; 431: 1112-1117Crossref PubMed Scopus (618) Google Scholar, 107.Chow E.K. et al.Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells.Hepatology. 2012; 56: 1331-1341Crossref PubMed Scopus (59) Google Scholar, 108.Huang C.H. et al.CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma.Genes Dev. 2014; 28: 1800-1814Crossref PubMed Scopus (99) Google Scholar]Melanoma and papilloma[109.Pelengaris S. et al.Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion.Mol. Cell. 1999; 3: 565-577Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar,110.Kfoury A. et al.AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress.EMBO J. 2018; 37e97673Crossref PubMed Scopus (19) Google Scholar]Neuroblastoma[111.Weiss W.A. et al.Targeted expression of MYCN causes neuroblastoma in transgenic mice.EMBO J. 1997; 16: 2985-2995Crossref PubMed Scopus (535) Google Scholar,112.Althoff K. et al.A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies.Oncogene. 2015; 34: 3357-3368Crossref PubMed Scopus (53) Google Scholar]Osteosarcoma[113.Jain M. et al.Sustained loss of a neoplastic phenotype by brief inactivation of MYC.Science. 2002; 297: 102-104Crossref PubMed Scopus (498) Google Scholar]Pancreatic cancer[114.Pelengaris S. et al.Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression.Cell. 2002; 109: 321-334Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar,115.Sodir N.M. et al.MYC Instructs and maintains pancreatic adenocarcinoma phenotype.Cancer Discov. 2020; 10: 588-607Crossref PubMed Scopus (12) Google Scholar]Prostate cancer[28.Kirschner A.N. et al.PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer.J. Natl. Cancer Inst. 2015; 107dju407Crossref PubMed Scopus (44) Google Scholar,116.Ellwood-Yen K. et al.Myc-driven murine prostate cancer shares molecular features with human prostate tumors.Cancer Cell. 2003; 4: 223-238Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar]Renal cell carcinoma[51.Shroff E.H. et al.MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 6539-6544Crossref PubMed Scopus (110) Google Scholar] Open table in a new tab Given the critical role of MYC as a cancer-driving oncogene, it is reasonable to conclude that MYC-addicted tumours benefit from abrogation of MYC function. In fact, several MYC-induced in vivo cancer models have demonstrated that the abrogation of MYC function was able to reverse the tumorigenesis process[94.Gabay M. et al.MYC activation is a hallmark of cancer initiation and maintenance.Cold Spring Harb. Perspect. Med. 2014; 4a014241Crossref PubMed Scopus (316) Google Scholar]. This has been observed across various haematological and solid cancers (Table I). The promise of MYC as a therapeutic target in MYC-driven cancers is therefore undeniable, prompting the development of potential MYC inhibitors.Table IDevelopment of MYC-Driven Mouse Cancer Models, Updated from Gabay et al. [94.Gabay M. et al.MYC activation is a hallmark of cancer initiation and maintenance.Cold Spring Harb. Perspect. Med. 2014; 4a014241Crossref PubMed Scopus (316) Google Scholar].Tumour typeMalignancyRefsHaematologicalT cell acute lymphoblastic leukaemia[102.Felsher D.W. Bishop J.M. Reversible tumorigenesis by MYC in hematopoietic lineages.Mol. Cell. 1999; 4: 199-207Abstract Full Text Full Text PDF PubMed Scopus (652) Google Scholar,103.Marinkovic D. et al.Reversible lymphomagenesis in conditionally c-MYC expressing mice.Int. J. Cancer. 2004; 110: 336-342Crossref PubMed Scopus (61) Google Scholar]B cell acute lymphoblastic leukaemia[103.Marinkovic D. et al.Reversible lymphomagenesis in conditionally c-MYC expressing mice.Int. J. Cancer. 2004; 110: 336-342Crossref PubMed Scopus (61) Google Scholar]Multiple myeloma[104.Chesi M. et al.AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies.Cancer Cell. 2008; 13: 167-180Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar]SolidBreast cancer[86.Lourenco C. et al.Modelling the MYC-driven normal-to-tumour switch in breast cancer.Dis. Model. Mech. 2019; 12Crossref PubMed Scopus (3) Google Scholar,105.D'Cruz C.M. et al.c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations.Nat. Med. 2001; 7: 235-239Crossref PubMed Scopus (0) Google Scholar]Liver cancers[106.Shachaf C.M. et al.MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.Nature. 2004; 431: 1112-1117Crossref PubMed Scopus (618) Google Scholar, 107.Chow E.K. et al.Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells.Hepatology. 2012; 56: 1331-1341Crossref PubMed Scopus (59) Google Scholar, 108.Huang C.H. et al.CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma.Genes Dev. 2014; 28: 1800-1814Crossref PubMed Scopus (99) Google Scholar]Melanoma and papilloma[109.Pelengaris S. et al.Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion.Mol. Cell. 1999; 3: 565-577Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar,110.Kfoury A. et al.AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress.EMBO J. 2018; 37e97673Crossref PubMed Scopus (19) Google Scholar]Neuroblastoma[111.Weiss W.A. et al.Targeted expression of MYCN causes neuroblastoma in transgenic mice.EMBO J. 1997; 16: 2985-2995Crossref PubMed Scopus (535) Google Scholar,112.Althoff K. et al.A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies.Oncogene. 2015; 34: 3357-3368Crossref PubMed Scopus (53) Google Scholar]Osteosarcoma[113.Jain M. et al.Sustained loss of a neoplastic phenotype by brief inactivation of MYC.Science. 2002; 297: 102-104Crossref PubMed Scopus (498) Google Scholar]Pancreatic cancer[114.Pelengaris S. et al.Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression.Cell. 2002; 109: 321-334Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar,115.Sodir N.M. et al.MYC Instructs and maintains pancreatic adenocarcinoma phenotype.Cancer Discov. 2020; 10: 588-607Crossref PubMed Scopus (12) Google Scholar]Prostate cancer[28.Kirschner A.N. et al.PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer.J. Natl. Cancer Inst. 2015; 107dju407Crossref PubMed Scopus (44) Google Scholar,116.Ellwood-Yen K. et al.Myc-driven murine prostate cancer shares molecular features with human prostate tumors.Cancer Cell. 2003; 4: 223-238Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar]Renal cell carcinoma[51.Shroff E.H. et al.MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 6539-6544Crossref PubMed Scopus (110) Google Scholar] Open table in a new tab Despite the critical role of MYC in cancer, targeting MYC has proved to be challenging for the past few decades. One reason is that MYC is a general transcription factor necessary in physiologically normal cells. Consequently, there may be severe off-target effects in normal tissues [1.Dang C.V. et al.Drugging the 'undruggable' cancer targets.Nat. Rev. Cancer. 2017; 17: 502-508Crossref PubMed Scopus (211) Google Scholar,7.Masso-Valles D. Soucek L. Blocking Myc to treat cancer: reflecting on two decades of Omomyc.Cells. 2020; 9: 883Crossref Google Scholar]. More importantly, as a nonenzymatic protein, MYC has an innately disordered structure with no fixed 3D conformation for the development of conventional small-molecule inhibitors [8.Jin F. et al.Ligand clouds around protein clouds: a scenario of ligand binding with intrinsically disordered proteins.PLoS Comput. Biol. 2013; 9e1003249Crossref PubMed Scopus (0) Google Scholar]. Hence, the pharmacological inhibition of MYC is a daunting task and MYC still remains clinically undruggable, leaving a dearth of therapeutic options for MYC-driven cancers. To circumvent the challenges that impede the development of direct MYC inhibitors, researchers have adopted synthetic lethality as a therapeutic strategy for MYC-dependent tumours by identifying vulnerabilities which can be exploited for cancer therapeutics. In the following, we examine various Achilles' heels of MYC-dependent cancers. Two broad groups of vulnerabilities in MYC-driven tumours have been identified based on the oncogenic properties of MYC – the mechanisms of MYC deregulation and downstream pathways of MYC which contribute to tumorigenesis (Figure 1, Key Figure). The elucidation of noncanonical sensitivities in MYC-driven tumours through large-scale genetic screens has also expanded the repertoire of synthetic lethal targets against MYC-driven tumours. This is significant as the typical functions of these noncanonical proteins are not innately oncogenic, and may be dismissed as nonessential for MYC-dependent carcinogenesis. In targeting MYC deregulation, the most straightforward strategy is to inhibit the expression of MYC. Two major components of the MYC transcription regulatory complex have been identified as synthetic lethal targets in MYC-driven cancers – bromodomain-containing protein (BRD)4 and cyclin-dependent kinase (CDK)9. Delmore et al. showed in vivo evidence for targeting MYC transcription by demonstrating that the BRD4 inhibitor, JQ1, could elicit a complete response in a mouse model of MYC-driven multiple myeloma [9.Delmore J.E. et al.BET bromodomain inhibition as a therapeutic strategy to target c-Myc.Cell. 2011; 146: 904-917Abstract Full Text Full Text PDF PubMed Scopus (1713) Google Scholar]. Numerous studies subsequently demonstrated that pharmacological inhibition of BRD4 was able to reduce MYC levels and impair MYC-driven cancers [10.Puissant A. et al.Targeting MYCN in neuroblastoma by BET bromodomain inhibition.Cancer Discov. 2013; 3: 308-323Crossref PubMed Scopus (368) Google Scholar,11.Mertz J.A. et al.Targeting MYC dependence in cancer by inhibiting BET bromodomains.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 16669-16674Crossref PubMed Scopus (723) Google Scholar]. The abrogation of CDK9 also led to the suppression of MYC and MYC transcriptional programmes, resulting in tumour regression in MYC-driven models of hepatocellular carcinoma and B cell lymphoma [12.Gregory G.P. et al.CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo.Leukemia. 2015; 29: 1437-1441Crossref PubMed Scopus (0) Google Scholar,13.Hashiguchi T. et al.Cyclin-dependent kinase-9 is a therapeutic target in MYC-expressing diffuse large B-cell lymphoma.Mol. Cancer Ther. 2019; 18: 1520-1532Crossref PubMed Scopus (10) Google Scholar]. Lu et al. further demonstrated that the concurrent inhibition of both CDK9 and BRD4 successfully impaired growth of cancer cells, showcasing the potential synergy of CDK9 and BRD4 inhibition [14.Lu H. et al.Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.Elife. 2015; 4e06535PubMed Google Scholar]. As a super-enhancer-associated oncogene, MYC transcription is also dependent on CDK7 activity in addition to BRD4 [15.Chipumuro E. et al.CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.Cell. 2014; 159: 1126-1139Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar,16.Loven J. et al.Selective inhibition of tumor oncogenes by disruption of super-enhancers.Cell. 2013; 153: 320-334Abstract Full Text Full Text PDF PubMed Scopus (1283) Google Scholar]. Pharmacological inhibition of CDK7 with a covalent inhibitor, THZ1, led to downregulation of MYC expression and significant tumour regression, supporting the role of CDK7 as a synthetic lethal target of MYC [15.Chipumuro E. et al.CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.Cell. 2014; 159: 1126-1139Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar]. Noticeably, susceptibility towards THZ1 was markedly more pronounced in cancers harbouring MYC deregulation [15.Chipumuro E. et al.CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.Cell. 2014; 159: 1126-1139Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar,17.Wang C. et al.A CRISPR screen identifies CDK7 as a therapeutic target in hepatocellular carcinoma.Cell Res. 2018; 28: 690-692Crossref PubMed Scopus (22) Google Scholar]. Apart from protein regulators of MYC expression, nucleic acid elements, such as the G-quadruplex (G4) in the MYC promoter offers a potential synthetic lethal target. Recent elucidation of small-molecule MYC G4 modulators has demonstrated that stabilisation of the MYC G4 is able to silence MYC expression substantially, leading to cell cycle arrest and senescence in multiple myeloma cells harbouring MYC lesions and overexpression [18.Felsenstein K.M. et al.Small molecule microarrays enable the identification of a selective, quadruplex-binding inhibitor of MYC expression.ACS Chem. Biol. 2016; 11: 139-148Crossref PubMed Scopus (68) Google Scholar,19.Gaikwad S.M. et al.A small molecule stabilizer of the MYC G4-quadruplex induces endoplasmic reticulum stress, senescence and pyroptosis in multiple myeloma.Cancers (Basel). 2020; 12: 2952Crossref Scopus (0) Google Scholar]. Targeting transcriptional control of MYC expression therefore offers a variety of synthetic lethal targets for MYC-driven cancers. Because MYC naturally has a short half-life, targeting modulators of MYC stability can promote the degradation of MYC and inhibit MYC-dependent cancers [20.Andresen C. et al.Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding.Nucleic Acids Res. 2012; 40: 6353-6366Crossref PubMed Scopus (59) Google Scholar]. Regulators of MYC stability include polo-like kinase 1 (PLK1), Pim-1, and aurora kinases A and B (AURKA and AURKB) [21.Xiao D. et al.Polo-like kinase-1 regulates Myc stabilization and activates a feedforward circuit promoting tumor cell survival.Mol. 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The synthetic lethal value of these proteins in MYC-driven cancers was demonstrated in several models of MYC-driven cancers, where inhibition of either of the four targets led to tumour suppression [21.Xiao D. et al.Polo-like kinase-1 regulates Myc stabilization and activates a feedforward circuit promoting tumor cell survival.Mol. Cell. 2016; 64: 493-506Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,25.Ren Y. et al.PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas.J. Clin. Invest. 2018; 128: 5517-5530Crossref PubMed Scopus (25) Google Scholar, 26.den Hollander J. et al.Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state.Blood. 2010; 116: 1498-1505Crossref PubMed Scopus (155) Google Scholar, 27.Mollaoglu G. et al.MYC drives progression of small cell lung cancer to a v