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Page 8 of 11 Zhang et al. J Cancer Metastasis Treat 2020;6:21 I http://dx.doi.org/10.20517/2394-4722.2020.40
[61]
activity . Furthermore, JQ1, a BET (bromodomain and extra-terminal domain) inhibitor, can also inhibit
[62]
MYC transcription, as well as other pathways . We and others have focused on interfering with MYC gene
transcription by an alternative inhibitory mechanism involving small molecules that stabilize complex DNA
structures (G-quadruplexes) which form transiently in the MYC promoter [26,27,63,64] .

Our studies to identify cooperative targets of mTORi/HDACi inhibition have: (1) provided a basic
approach for broader application to identify potential biomarkers of drug combinations utilizing weighted
gene coexpression network analyses combined with gene set enrichment analyses of survival annotated
patient datasets; (2) identified upstream regulators/drivers of drug responses leading to a mechanistic
understanding of how the combination is acting (upregulation of tumor suppressive pathways (Rb1 and
p16) and downregulation of oncogenic pathways (MYC and E2F1), leading to MYC degradation; and (3)
demonstrated that cell lines carrying mutations in FBXW7 or surrounding MYC residues Thr58,Ser62,
involved in MYC degradation are not likely to respond to the combination of rapamycin/everolimus and
entinostat. While MYC is known to be deregulated in a majority of cancers, its direct drug targeting has
been elusive. We hope that our work to identify and develop a new class of compounds targeting MYC
transcription will lead to new pharmacological agents for MYC inhibition. Our studies suggest that it
would be clinically useful if these inhibitors were coupled with drugs that simultaneously upregulate tumor
suppressors. Our studies are designed to provide the pre-clinical rationale and evidence of synergistic
mechanisms required to advance candidate combinations for preclinical assessment in patient-derived cells
and eventually in clinical study.

DECLARATIONS
Acknowledgments
We wish to thank our many collaborators and lab members for their contributions to the primary research
referenced in this review: Douglas Lowy, Aleksandra Michalowski, Jyoti Patel, Patrick Sullivan, John S.
Schneekloth, Jr., David Calabrese, Michael Kuehl, Ola Landgren, Robert Hawley, Anaisa Quintanilla-
Arteaga, Patricia Wiley, Nana Gayabah-Kessie, Kenneth Felsenstein, Elena Leon, Zaw Phyo, Daniel
Connors, Ben Gamache, Nick Watson, Max Eiden, Matt Steinsaltz, Maudeline Etienne, Joy Gary, Edward
Ramsey, Marianne Krall, Cecilia Padlan, Danielle Holiday, Jenefer Dosik, Margaret Pruitt, Dena Tran,
Siegfried Janz, Alexander Kovalchuk, Elizabeth Mushinski, Mari Hirano, Rania Salem, Jing Huang, and
R. Mark Simpson. We also thank Richard Nordan, Michael Potter, J. Frederic Mushinski, and Valery
Bliskovsky (in memoriam) for their many contributions to these studies.

Authors’ contributions
Made conceptual contributions to the manuscript: Zhang S, DuBois W, Zhang K, Simmons JK, Hughitt VK,
Gorjifard S, Gaikwad S, Peat TJ, Mock BA
Wrote the manuscript: Simmons JK, Hughitt VK, Gorjifard S, Gaikwad S, Peat TJ, Mock BA
Designed several of the figures: Gorjifard S

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by the Intramural Research Program of the National Institutes of Health, National
Cancer Institute, Center for Cancer Research and the MMRF (Multiple Myeloma Research Foundation).

Conflicts of interest
All authors declared that there are no conflicts of interest.