Abstract IA25: MYC as therapeutic target

Overexpression of the MYC proto-oncogene is a common genetic malfunction in various human cancers. This makes the gene product of MYC (Myc) a potentially attractive target for therapeutics. Several issues, however, undermine that attractiveness. First, the tumorigenic culprit is usually a normal allele of MYC. There is no distinguishing feature that might facilitate specificity in therapeutic targeting. Second, MYC is a vital gene in most cells. Therapeutic reduction of its function may require exacting titration. Third, “drugging” of Myc has proven to be difficult and has yet to be reduced to practice. There are at least two ways to attack the overexpression of MYC without directly targeting its function. First, Myc represents a nexus in multiple signaling pathways, making its effect vulnerable to inhibition of functions either upstream or downstream of the nexus. For example, there is some promise in inhibiting a bromodomain protein that facilitates expression of MYC, although this approach may still require careful titration of the inhibition. Second, it is possible to exploit the overexpression of Myc by utilizing synthetic lethal interactions with the inhibition of other gene products. This approach may circumvent the several limitations posed by Myc as a therapeutic target. We have explored three distinctive synthetic lethal interactions with the overexpression of Myc, utilizing both cell lines in vitro and mouse models in which a MYC transgene drives tumorigenesis. 1.) Inhibition of the cdk1 cell cycle kinase, which is reversible with normal cells, but elicits vigorous apoptosis in cells that overexpress Myc. The efficacy of this in preclinical studies has led to a Phase 1b trial with triple-negative breast cancer, in which MYC is commonly overexpressed. 2.) Inhibition of the Aurora B kinase, which is also reversible in normal cells, but kills cells that overexpress Myc by means of both apoptosis and autophagy. We have examined the resistance to this therapy that eventually emerges in a MYC-driven liver cancer. As expected, Aurora B kinase has become resistant to the drug in vivo. But there is also a surprising reduction in nuclear Myc, although the tumors remain dependent upon Myc function. 3.) Inhibition of glutaminase. We have found that overexpression of MYC can reconfigure intermediary metabolism in a way that makes at least some forms of tumors exquisitely dependent upon glutamine. In this setting, deprivation of glutamine by inhibition of glutaminase elicits a strong synthetic lethal interaction not displayed by normal cells. It is widely suspected that cancer stem cells possess inherent chemoresistance that allows them to replenish tumors after they have been diminished by chemotherapy. We have identified a small subpopulation of cells in a Myc-driven liver cancer that are enriched for tumor-initiating capacity and display chemoresistance implemented by the MDR1 transporter. This subpopulation can continuously generate “mature” tumor cells, which no longer express MDR1 and have lost the drug resistance. When utilized early in the course of tumorigenesis, the synthetic lethal interaction with Myc elicited by inhibition of Aurora B kinase can eradicate all evidence of tumor-initiating capacity. Our results with MYC exemplify the potential utility of synthetic lethality as a general approach to cancer therapy. It offers a means to attack otherwise recalcitrant targets (including loss of function by tumor suppressor genes), it can substantially diversify the attack on a particular genetic malfunction, and it may have exceptional utility for the eradication of cancer stem cells. Note: This abstract was not presented at the conference. Citation Format: J. Michael Bishop. MYC as therapeutic target. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA25.