Modelling Myc inhibition as a cancer therapy

By L. Soucek, J. Whitfield, C. Martins, A. Finch, Daniel J. Murphy, N. Sodir, A. Karnezis, L. Swigart, S. Nasi, G. Evan. Nature, 2008

845 citations recorded by the source corpus.

Myc is a pleiotropic basic helix–loop–helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.

Subfields: Molecular Biology, Oncology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/0ea29f10e1d5f36ded7d6b88adc86211d96dd885

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Hongbo Chi

Citations in the corpus

Transcriptional Amplification in Tumor Cells with Elevated c-Myc (2012, positive): “MYC is a potent oncogene that can promote tumorigenesis in a wide range of tissues (Felsher and Bishop, 1999; Flores et al., 2004; Jain et al., 2002; Pelengaris et al., 1999; Sodir et al., 2011; Soucek et al., 2008; Verbeek et al., 1991).”
KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer (2018, background): “An important growth-promoting ERK substrate is the tran- scription factor MYC (Farrell and Sears 2014), an oncoprotein required for maintenance of RAS-driven tumors (Soucek et al. 2008).”
Biological determinants of endocrine resistance in breast cancer (2009, background): “Recent evidence indicates that targeting MYC may be an effective cancer therap”
The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation (2011, result): “We observed that acute depletion of Myc, in vivo, did not compromise the health of the animals over a period of 1 week, consistent with a recent report (Soucek et al., 2008).”
MYC on the Path to Cancer (2012, background): “In fact, expression of a dominant-negative inhibitor of Myc heterodimerization in vivo has resulted in tumor regression, suggesting that inhibiting Myc function could be a feasible therapeutic strategy (Soucek et al., 2008).”
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia (2011, background): “27 ), which has been validated as an attractive therapeutic target but has thus far escaped efforts at pharmacological inhibitio”
Senescence in tumours: evidence from mice and humans (2010, background): “This is the case for KRAS G12D -initiated lung carcinomas, in which inactivation of the three Myc paralogues, MYC, MYCN and MYCL1, by an artificial dimerization partner known as Omomyc, results in tumour regression in association with apoptosis and senescenc”
Awakening guardian angels: drugging the p53 pathway (2009, background): “The lack of toxicity of a temporary cell cycle arrest in the normal tissues of an adult mouse has been demonstrated by Gerard Evan's laboratory with an inducible dominant-negative MYC inhibito”
Transcriptional Addiction in Cancer (2017, positive): “Research in model systems of MYC addiction and withdrawal have validated addiction to this master regulatory transcription factor in solid and hematologic malignancies, both with and without structural changes to the MYC locus itself (Felsher and Bishop, 1999; Jain et al., 2002; Soucek et al., 2008;”
Guidelines for the welfare and use of animals in cancer research (2010, background): “As a consequence of extensive in vitro testing, comparatively small numbers of prioritised compounds progress to examination in vivo (Collins and Workman, 2006).”
MYC activation is a hallmark of cancer initiation and maintenance. (2014, background): “Using a dominant negative MYC, designated “omoMYC,” investigators illustrated that conditional suppression of MYC appears to reverse RAS-induced tumorigenesis (Soucek et al. 2008, 2013).”