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Zhang et al. J Cancer Metastasis Treat 2020;6:21 Journal of Cancer
DOI: 10.20517/2394-4722.2020.40 Metastasis and Treatment

Review Open Access

Mouse tumor susceptibility genes identify drug
combinations for multiple myeloma

Shuling Zhang , Wendy DuBois , Ke Zhang , John K. Simmons , V. Keith Hughitt , Sayeh Gorjifard ,
1
1
1,2
1,3
1
1
Snehal Gaikwad , Tyler J. Peat , Beverly A. Mock 1
1
1
1 Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA.
2 Personal Genome Diagnostics, Baltimore, MD 21224, USA.
3 University of Washington School of Medicine, Department of Genome Sciences, Seattle, WA 98195, USA.
Correspondence to: Dr. Beverly A. Mock, Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, 37 Convent Dr., Bldg. 37,
Rm 3146, Bethesda, MD 20892, USA. E-mail: mockb@mail.nih.gov
How to cite this article: Zhang S, DuBois W, Zhang K, Simmons JK, Hughitt VK, Gorjifard S, Gaikwad S, Peat TJ, Mock BA. Mouse
tumor susceptibility genes identify drug combinations for multiple myeloma. J Cancer Metastasis Treat 2020;6:21.
http://dx.doi.org/10.20517/2394-4722.2020.40
Received: 5 Mar 2020 First Decision: 17 Jun 2020 Revised: 3 July 2020 Accepted: 7 Jul 2020 Published: 26 Jul 2020

Academic Editor: Ciro Isidoro Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

Abstract
Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning
strategies and functional studies identified Cdkn2a, Mtor, and Mndal as mouse plasmacytoma susceptibility/
resistance genes. Tumor incidence data in congenic strains carrying the resistance alleles of Cdkn2a and Mtor led
us to hypothesize that drug combinations affecting these pathways are likely to have an additive, if not synergistic
effect in inhibiting tumor cell growth. Traditional and novel systems-level genomic approaches were used to
assess combination activity, disease specificity, and clinical potential of a drug combination involving rapamycin/
everolimus, an Mtor inhibitor, with entinostat, an histone deacetylase inhibitor. The combination synergistically
repressed oncogenic MYC and activated the Cdkn2a tumor suppressor. The identification of MYC as a primary
upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in
the NHEIII region of the MYC promoter. These studies highlight the importance of identifying drug combinations
which simultaneously upregulate tumor suppressors and downregulate oncogenes.

Keywords: Complex genetic trait, plasma cell tumor, multiple myeloma, entinostat, rapamycin, drug combinations,
Cdkn2a, Mtor, Mndal, MYC

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
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