Capitalizing on Synthetic Lethality of MYC to Treat Cancer in the Digital Age

Thng, Dexter Kai Hao; Toh, Tan Boon; Chow, Edward Kai‐Hua

doi:10.1016/j.tips.2020.11.014

Cited by 40 publications

(51 citation statements)

References 115 publications

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“…These include synthetic lethal approaches that could in theory target any specific dependence of Myc-driven tumor cells. Many diverse targets have already been identified, including SAE1/2 ( Kessler et al, 2012 ), CDK2 ( Hydbring and Larsson, 2010 ), CDK9 ( Huang et al, 2014 ), PIM kinase ( Horiuchi et al, 2016 ), and many more involved in metabolism (for a more complete discussion, see Thng et al [2021] ; Whitfield et al [2017] ). One advantage for this group is that novel synthetic lethal targets may already have a clinically approved inhibitor that could be quickly exploited for use in Myc-driven cancers.…”

Section: Synthetic Lethalitymentioning

confidence: 99%

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The long journey to bring a Myc inhibitor to the clinic

Whitfield¹,

Soucek

2021

Journal of Cell Biology

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The oncogene Myc is deregulated in the majority of human tumors and drives numerous hallmarks of cancer. Despite its indisputable role in cancer development and maintenance, Myc is still undrugged. Developing a clinical inhibitor for Myc has been particularly challenging owing to its intrinsically disordered nature and lack of a binding pocket, coupled with concerns regarding potentially deleterious side effects in normal proliferating tissues. However, major breakthroughs in the development of Myc inhibitors have arisen in the last couple of years. Notably, the direct Myc inhibitor that we developed has just entered clinical trials. Celebrating this milestone, with this Perspective, we pay homage to the different strategies developed so far against Myc and all of the researchers focused on developing treatments for a target long deemed undruggable.

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Section: Synthetic Lethalitymentioning

confidence: 99%

“…One advantage for this group is that novel synthetic lethal targets may already have a clinically approved inhibitor that could be quickly exploited for use in Myc-driven cancers. To date, there are few approved options, but many more are in current clinical trials ( Thng et al, 2021 ).…”

Section: Synthetic Lethalitymentioning

confidence: 99%

The long journey to bring a Myc inhibitor to the clinic

Whitfield¹,

Soucek

2021

Journal of Cell Biology

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“…This renders cancer cells with deregulated MYC particularly sensitive to inhibitors of such pathways. The existence of MYC-associated synthetic dosage lethality is well documented by unbiased genetic and pharmacological screening experiments [39] and is relevant in the context of PDAC [21]. Genes allowing to tolerate MYC-induced oncogenic stress may be involved in feedforward regulatory circuits and blocking of such a gene also impacts on MYC expression.…”

Section: Myc Stratifies For Therapiesmentioning

confidence: 99%

Rationale for MYC imaging and targeting in pancreatic cancer

et al. 2021

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The incidence and lethality of pancreatic ductal adenocarcinoma (PDAC) will continue to increase in the next decade. For most patients, chemotherapeutic combination therapies remain the standard of care. The development and successful implementation of precision oncology in other gastrointestinal tumor entities point to opportunities also for PDAC. Therefore, markers linked to specific therapeutic responses and important subgroups of the disease are needed. The MYC oncogene is a relevant driver in PDAC and is linked to drug resistance and sensitivity. Here, we update recent insights into MYC biology in PDAC, summarize the connections between MYC and drug responses, and point to an opportunity to image MYC non-invasively. In sum, we propose MYC-associated biology as a basis for the development of concepts for precision oncology in PDAC.

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“…6,7 Different strategies are applied to overcome the challenges, such as synthetic lethality that counts on gene pairs. 8 Alternatively, gene therapy has attracted increasing attention due to the capability of specifically controlling the expression of disease-related proteins.…”

Section: Introductionmentioning

confidence: 99%