Targeting Synthetic Lethal Interactions between Myc and the eIF4F Complex Impedes Tumorigenesis

Lin, Chen‐Ju; Nasr, Zeina; Premsrirut, Prem K.; Porco, John A.; Hippo, Yoshitaka; Lowe, Scott W.; Pelletier, Jerry

doi:10.1016/j.celrep.2012.02.010

Cited by 81 publications

(90 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In melanoma, our finding that MYC is a nexus of convergent resistance is consistent with a recent report that used network modeling to nominate MYC as a synergistic target with BRAF, then verified this finding by demonstrating synergy between JQ1 and vemurafenib treatment in a cell line (Korkut et al, 2015). Our findings are also interesting in light of a report suggesting that the eukaryotic initiation factor 4F (eIF4F) complex may act as a point of convergence between the ERK and PI3K resistance pathways in melanoma, as MYC and eIF4F interact in a well-characterized synthetic lethal feedforward loop to support tumorigenesis (Boussemart et al, 2014; Lin et al, 2008; Lin et al, 2012). The molecular mechanisms by which MYC is regulated by the major pathways of resistance in melanoma are therefore important areas for future study.…”

Section: Discussionmentioning

confidence: 54%

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

et al. 2017

View full text Add to dashboard Cite

SUMMARY Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of over 20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

show abstract

Section: Discussionmentioning

confidence: 54%

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

et al. 2017

View full text Add to dashboard Cite

show abstract

“…One of the major and immediate downstream effects of Myc activation is a dramatic increase in the protein synthetic capacity of the cell that results in increased cell survival, proliferation, and genome instability (7)(8)(9). Importantly, genetically restoring enhanced protein synthesis to normal levels downstream of Myc suppresses tumor development (10), suggesting that modulating protein synthesis control may be a promising therapeutic approach (11)(12)(13). However, the components of the translation machinery that can be therapeutically targeted to exploit the addiction of Myc-driven cancer cells to augmented protein synthesis remain largely undefined.…”

Section: Neurosciencementioning

confidence: 99%

Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Pourdehnad

Truitt

Siddiqi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

228

213

View full text Add to dashboard Cite

Myc is one of the most commonly deregulated oncogenes in human cancer, yet therapies directly targeting Myc hyperactivation are not presently available in the clinic. The evolutionarily conserved function of Myc in modulating protein synthesis control is critical to the Myc oncogenic program. Indeed, enhancing the protein synthesis capacity of cancer cells directly contributes to their survival, proliferation, and genome instability. Therefore, inhibiting enhanced protein synthesis may represent a highly relevant strategy for the treatment of Myc-dependent human cancers. However, components of the translation machinery that can be exploited as therapeutic targets for Myc-driven cancers remain poorly defined. Here, we uncover a surprising and important functional link between Myc and mammalian target of rapamycin (mTOR)-dependent phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 (4EBP1), a master regulator of protein synthesis control. Using a pharmacogenetic approach, we find that mTOR-dependent phosphorylation of 4EBP1 is required for cancer cell survival in Myc-dependent tumor initiation and maintenance. We further show that a clinical mTOR active site inhibitor, which is capable of blocking mTOR-dependent 4EBP1 phosphorylation, has remarkable therapeutic efficacy in Myc-driven hematological cancers. Additionally, we demonstrate the clinical implications of these results by delineating a significant link between Myc and mTOR-dependent phosphorylation of 4EBP1 and therapeutic response in human lymphomas. Together, these findings reveal that an important mTOR substrate is found hyperactivated downstream of Myc oncogenic activity to promote tumor survival and confers synthetic lethality, thereby revealing a unique therapeutic approach to render Myc druggable in the clinic.

show abstract

“…Analogous cofactors have also been identified, and some are being developed as therapeutic targets (Goga et al 2007;Zuber et al 2011c;Kessler et al 2012;Lin et al 2012a;Toyoshima et al 2012). For example, BRD4 was identified as a therapeutic target for acute myeloid leukemia and other blood cancers by virtue of its ability to sustain MYC transcription, and small molecule BRD4 inhibitors show potent anti-leukemic effects (Dawson et al 2011;Delmore et al 2011;Zuber et al 2011c).…”

Section: Discussionmentioning

confidence: 99%

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

et al. 2014

View full text Add to dashboard Cite

One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.

show abstract

Targeting Synthetic Lethal Interactions between Myc and the eIF4F Complex Impedes Tumorigenesis

Cited by 81 publications

References 46 publications

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

Contact Info

Product

Resources

About