The promise of molecular targeted therapy for cancer is to provide selective killing of tumor cells while sparing normal cells. Targeted therapy, however, requires that the oncogenic pathways activated in tumor cells can be defined, and that selective inhibitors can be found to abrogate these pathways. One major limitation to targeted therapeutic approaches is that many oncogenic pathways, especially those involving transcription factors, cannot be directly inhibited with small molecule compounds. An alternative approach is to use small molecule inhibitors that target basic cellular processes, such as the cell cycle, which merely arrest normal cells, but which in combination with activation of particular oncogenic pathways result in synthetic-lethal combinations. Cyclin-dependent kinases (CDKs) are a conserved family of protein kinases that play a central role in regulating the eukaryotic cell cycle. CDK1 and CDK2 are thought to be particularly important for driving the major cell cycle events in normal and neoplastic mammalian cells and these kinases might therefore be important targets for cancer therapy. The overall hypothesis that is being tested is whether inhibition of different CDKs can result in selective killing of tumor versus normal cells. (1) We seek to determine the genetic context in which cells are rendered especially sensitive to CDK inhibitors, resulting in cell death or another abortive cell cycle program. (2) We seek to determine how MYC oncogene over- expression sensitizes to cell death following CDK1 inhibition. (3) We seek to understand the molecular basis for cell death induced by CDK inhibition. To accomplish our goals we will utilize two complementary approaches to address this question. Both conventional small-molecule CDK inhibitors as well as a chemical-genetic approach will be employed to identify the genetic context in which CDK inhibitors may prove to be useful therapeutics. Our hypothesis, if confirmed, will significantly improve our understanding of how CDK inhibitors may be useful to target specific oncogenic pathways and should lead to novel therapeutics for cancer.
Normal cellular proliferation requires an orderly progression through the cell cycle that involves multiple regulatory enzymes. In contrast, cancer cells proliferate inappropriately and without end resulting in a tumor mass. Since tumor cells proliferate inappropriately, precise inhibition of the cell cycle may lead to the death of tumor cells while normal cells may be spared. The goal of this proposal is to determine if selective inhibition of cell cycle regulatory enzymes, known as cyclin-dependent kinases (CDKs), can cause the arrest or perhaps death of tumor cells. The knowledge gained from these studies will facilitate the development of new therapeutics that target tumor cells with particular genetic changes by precisely inhibiting the cell division cycle.
|Horiuchi, Dai; Anderton, Brittany; Goga, Andrei (2014) Taking on challenging targets: making MYC druggable. Am Soc Clin Oncol Educ Book :e497-502|
|Lim, Lionel; Balakrishnan, Asha; Huskey, Noelle et al. (2014) MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer. Hepatology 59:202-15|
|Benjamin, Daniel I; Louie, Sharon M; Mulvihill, Melinda M et al. (2014) Inositol phosphate recycling regulates glycolytic and lipid metabolism that drives cancer aggressiveness. ACS Chem Biol 9:1340-50|
|Horiuchi, Dai; Huskey, Noelle E; Kusdra, Leonard et al. (2012) Chemical-genetic analysis of cyclin dependent kinase 2 function reveals an important role in cellular transformation by multiple oncogenic pathways. Proc Natl Acad Sci U S A 109:E1019-27|
|Horiuchi, Dai; Kusdra, Leonard; Huskey, Noelle E et al. (2012) MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J Exp Med 209:679-96|
|Chow, Edward K; Zhang, Xue-Qing; Chen, Mark et al. (2011) Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment. Sci Transl Med 3:73ra21|
|Hu, Simon; Balakrishnan, Asha; Bok, Robert A et al. (2011) 13C-pyruvate imaging reveals alterations in glycolysis that precede c-Myc-induced tumor formation and regression. Cell Metab 14:131-42|
|Merrick, Karl A; Wohlbold, Lara; Zhang, Chao et al. (2011) Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation. Mol Cell 42:624-36|
|Swarbrick, Alexander; Woods, Susan L; Shaw, Alexander et al. (2010) miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nat Med 16:1134-40|