Kinase-Mediated Regulation of 40S Ribosome Assembly in Human Breast Cancer
Abstract
Our research team is dedicated to finding new ways to eradicate otherwise refractory subtypes of breast cancer. In particular, we are focusing our current efforts on the triple-negative breast cancer (TNBC) subtype, which afflicts 15%-25% of patients, has a dismal prognosis, and lacks effective therapies. The major goal of our studies is to define how the uncontrolled cell growth of this tumor type can be stopped in its tracks. In our quest to develop new therapeutic agents, we discovered that new in-house small molecule inhibitors of casein kinase-1-delta (CK1d), a protein that phosphorylates other proteins (that is, a kinase), had very potent and selective anticancer activity against TNBC cells in culture; treatment of TNBC cells with these inhibitors immediately blocked their growth and then triggered cell death. Our studies then showed that the gene encoding CK1d (CSNK1D) is amplified (that is, there are extra copies of the genomic region that contains CSNK1D) in up to 50% of TNBC tumors. Then, using genetic approaches that allow one to selectively suppress the expression of any given gene, we showed that reducing CK1d levels also compromised the growth and survival of TNBC. We then went on to show that inhibition of CK1d kinase activity or suppressing CK1d levels provokes the regression of TNBC tumors. Notably, recent work by our two labs, in collaboration with the investigator who created these CK1d inhibitors (Dr. William Roush, Professor of Chemistry, Scripps Florida), suggest that the essential function of CK1d is as a regulator of the assembly of ribosomes, which are large structures that serve as scaffolds for the synthesis of the proteins, a process that is in overdrive in cancer cells. Accordingly, our Breakthrough studies will test if the anti-cancer activity of these new CK1d inhibitors relies on their ability to disrupt the ribosome assembly. This, in turn, leads to the accumulation of ribosome intermediates that are destroyed, resulting in reduced numbers of ribosomes and proteins that are necessary for tumor cell growth and survival. Importantly, we submit that our studies will validate the entire ribosome assembly pathway as a target for the development of novel anti-cancer agents. Given the large number of assembly factors (~200) that are necessary for ribosome production, this pathway provides ample opportunities for developing new anti-cancer drugs. Further, we also are exploring new ways to augment the potency of our CK1d inhibitors by using Food and Drug Administration (FDA)-approved drugs that augment the activity of the autophagy pathway, the principal recycling center that normally degrades defective ribosome intermediates. While our proposed studies focus on TNBC, they are also likely highly relevant to other breast cancer subtypes that we have shown overexpress CK1d, including HER2-positive and estrogen receptor-positive Luminal B breast cancer, which are also more-difficult-to-treat breast cancer subtypes. Further, we suspect that disrupting the CK1d-to-ribosome assembly pathway will be safe as treatments for women with TNBC, as we can give our CK1d inhibitors to mice daily long term without ill side effects. Moreover, these CK1d inhibitors are selective, as they only inhibit tumor types that overexpress this kinase. For example, normal human breast epithelial cells and the ER+ luminal A subtype of breast cancer, which express very low levels of CK1d, are not affected by our in-house inhibitors. Nonetheless, others have shown that all forms of cancer are addicted to the overproduction of ribosomes, and it is thus likely that additional tumor types will display sensitivity to CK1d inhibitors. There are several clinical applications of our Breakthrough studies. First, the proposed studies will validate the CK1d-to-ribosome assembly pathway as an exploitable vulnerability for TNBC, which would support efforts for fast-tracking such CK1d-selective agents into the breast oncology
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610009
Entities
People
- John Cleveland
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army