Targeting MYC in Human Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Dai Horiuchi, Ph.D. -
Award Cycle: 2009 (Cycle 15) Grant #: 15FB-0006 Award: $90,000
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2009)

The MYC proto-oncogene is an essential gene that plays a key role in mammalian cell proliferation. As a transcription factor MYC regulates expression of nearly 1/3 of the genes in the human genome. Abnormal MYC amplification has been found in ~50% of human breast cancers including those that are hormone receptor-negative. MYC amplification has also been linked to resistance to the existing therapies and to decreased breast cancer patients’ survival. However, no targeted therapy currently exists to treat these difficult-to-cure breast cancers with high MYC levels. We recently discovered a “synthetic-lethality” in which CDK1 inhibition using a small molecule inhibitor sensitized a variety of cells engineered to over-express MYC to undergo apoptosis while normal cells are spared. This raises the possibility that essential gene products including those, like MYC, that cannot be directly targeted may be able to be “indirectly” targeted in drug-based cancer therapeutics. This proposed research seeks to establish CDK1 inhibition as a novel approach to specifically target breast cancer cells with high MYC levels.

We seek to test the hypothesis that MYC level predicts the responsiveness of breast cancers to CDK1 inhibition. The first aim is to define the correlation between MYC levels and the effectiveness of CDK1 inhibition in killing human breast cancer cells. The next aim is to analyze the mechanism by which CDK1 inhibition induces cell death. Finally, we plan to study the signaling mechanism that controls CDK1 inhibition-induced apoptosis in breast cancer cells with high MYC levels. For these studies, I will use a collection of 51 breast lines established from human primary breast tumors. We believe that the use of these cell lines allows us to examine our hypothesis in the context of heterogeneous human breast cancers, and that the outcomes will be more translatable into developing novel treatment strategies. Our technologies and functional studies include: (1) a high-throughput cell viability assay to define the correlation between MYC level and the response to CDK1 inhibition in inducing cell death, (2) a variety of cell-based assays to examine the modes of cell death, and (3) the function of apoptotic proteins and the signaling pathways that regulate them in CDK1 inhibition-induced apoptosis in breast cancer cells with high MYC.

Myc-over-expression has been implicated in breast tumor formation and their maintenance, and it is correlated with decreased patient survival. Thus, investigating this novel synthetic lethality between MYC levels and CDK1 inhibition in breast cancer cells may lead to the development of novel therapeutic approaches for the treatment of “difficult-to-cure” human breast cancers with high MYC.

Final Report (2011)

Estrogen, progesterone and HER2 receptor negative, "triple-negative" (TN) breast cancers encompass the most clinically challenging sub-type, for which no targeted therapeutics strategies are currently available in clinic. Thus, our long-term goals are to molecularly dissect what TN breast cancers are (i.e., to understand what makes TN breast cancers what they are), to identify druggable targets, and to establish novel therapeutic strategies against them.

First, we performed extensive molecular analysis on a large set of primary human breast tumor samples collected through an NCI-funded multi-institutional clinical study (I-SPY). In such effort, we identified oncogenic signaling pathways driven by a well-known proto-oncogene MYC as what might make TN tumors what they are. We also showed that a panel of TN breast cancer cell lines exhibiting elevated MYC expression was sensitive to a small molecule inhibition of the mitotic kinase CDK1. This is based on our previous finding that, while an essential transcription factor MYC itself cannot be directed inhibited by any existing means, inhibiting CDK specifically in the context of MYC overexpression induced cell death without affecting non-tumorigenic cells. This form of cell death induced by an indirect inhibition of another protein (i.e., CDK1, instead of MYC) is referred to as "synthetic-lethality". Finally, we showed that the cellular mechanisms of such MYC-CDK1 synthetic-lethality involved an activation of a pro-apoptotic factor BIM.

Next, we first evaluate the prognostic significance of MYC by analyzing clinical data. This is to study whether or not having tumors with elevated MYC expression indeed matters clinically. Our results show that elevated MYC expression predicts worse outcome in neo-adjuvant chemotherapy, raising the necessity for more "personalized" treatment strategies to be developed. We then further clarify the issue of selectivity regarding the use of CDK inhibitors using in vitro cell culture models. Our results show that TN cancer cells with elevated MYC expression are significantly more sensitive to CDK inhibition compared to ER/PR receptor-positive cells with low MYC expression. Finally, using mouse xenograft models, we demonstrated that small molecule inhibition of CDK is effective in killing tumor cells in mice, further supporting the utility for these types of inhibitors for treating TN tumors.

MYC pathway activation in triple-negative breast cancer is synthetic-lethal with CDK inhibition.
Periodical:Journal of Experimental Medicine
Index Medicus: J Exp Med
Authors: Horiuchi, D., Kusdra, L., Huskey, N.E., Chandriani, S., Lenburg, M.E., Gonzalez-Angulo, A.
Yr: Vol: 209 Nbr: Abs: Pg:679-696

Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation.
Periodical:Molecular Cell
Index Medicus: Mol Cell
Authors: Merrick KA, Wohlbold L, Zhang C, Allen JJ, Horiuchi D, et al
Yr: 2011 Vol: 42 Nbr: 5 Abs: Pg:624-36