Abstract S5-4: Synthetic-Lethality of Triple-Negative Breast Cancers Via the MYC Oncogene Pathway
| Autor: | Noelle E. Huskey, Dai Horiuchi, LJ Esserman, Sarah E. Davis, Andrei Goga, Marc E. Lenburg, Gordon B. Mills, Ana M. Gonzalez-Angulo, S Chandriani, Katelyn J. Creasman, Leonard Kusdra |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Cancer Research. 70:S5-4 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.sabcs10-s5-4 |
| Popis: | Background: Breast cancer lacking the estrogen, progesterone and ERBB2 receptors, (“triple-negative”) encompasses an aggressive sub-type that is associated with a higher incidence of early tumor recurrence and poor patient outcome, particularly after distant relapse. The lack of validated targets means that only conventional cytotoxic chemotherapy offers significant benefits, albeit with associated toxicities and lack of specificity. Among many potential therapeutic targets in triple-negative breast cancer, MYC may be important as its function is elevated in many breast cancers with aggressive phenotypes. Methods: In this study we investigate the association between MYC abundance in primary breast tumors using two large clinical cohorts and examined MYC mRNA and protein abundance as well as the expression of a MYC gene signature. We next examined the association between the MYC gene signature and patient response to neoadjuvant chemotherapy as well as disease-free survival in the ISPY TRIAL. Furthermore, we examined whether high MYC expression in triple-negative tumors might provide a new therapeutic approach in this tumor sub-type. We tested a synthetic-lethal strategy to kill triple-negative breast cells with abundant MYC expression by inhibiting cyclin-dependent kinases (CDKs). Results: We find that human triple-negative breast cell lines have significantly elevated MYC mRNA and protein expression. These results were validated using primary patient tumor samples from the neoadjuvant ISPY TRIAL (N= 138 patients) as well as a separate cohort of primary tumor samples for which quantitative protein expression was determined (N= 208 patients). In the ISPY TRIAL an increased expression of the MYC gene signature was associated with worse outcome in patients with substantial residual tumor burden after neoadjuvant chemotherapy (RCB Class II and III). We sought to exploit this increased MYC activity in triple-negative tumors using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. We found that triple-negative breast tumor cells undergo cell death in a MYC-dependent manner following treatment with several CDK inhibitors, including SCH72796 that is in Phase II clinical trials. We find that CDK inhibition effectively induces tumor regression in human tumor xenografts. CDK inhibition in triple-negative breast cells up-regulates the pro-apoptotic BCL2 family member BIM. Our findings support the exploration of CDK inhibitors as treatment for triple-negative breast cancers. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S5-4. |
| Databáze: | OpenAIRE |
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