88P - Targeting unique metabolic vulnerabilities in dormant ER+ tumor cells

Date 07 May 2015
Event IMPAKT 2015
Session Welcome reception and Poster Walk
Topics Basic Science
Breast Cancer
Presenter Erik Knudsen
Citation Annals of Oncology (2015) 26 (suppl_3): 29-30. 10.1093/annonc/mdv120
Authors E. Knudsen1, J. Franco2, A.K. Witkiewicz2
  • 1Pathology And Cancer Center, University of Texas Southwestern Medical Center, 75390 - Dallas/US
  • 2Pathology, University of Texas Southwestern Medical Center at Dallas, 75390 - Dallas/US



Purpose: In general cells that exited the cell cycle are resistant to conventional cytotoxic therapies. This represents one of the seminal challenges in eliminating the reservoir for disease recurrence that is particularly problematic in the context of ER+ breast cancer. Here we investigated metabolic features and resultant therapeutic sensitivities that are unique to induced dormancy.

Methods: Therapy induced dormancy was mediated using ER antagonists (e.g. Fulvestrant) and CDK4/6 inhibitors (e.g. PD-0332991) in models of ER+ positive breast cancer. These models were subjected to Mass-spectromety and metabolomics analysis to define the metabolic state in dormancy. Drug screens were used to define unique sensitivities that are imparted in non-proliferative cancer cells to delineate novel means of eliminate dormant cancer cells.

Results: In models of ER+ breast cancer endocrine therapy and CDK4/6 inhibition were effective at suppressing proliferation, but elicited surprisingly distinct effects on tumor metabolism. Endocrine therapy limited glycolytic and oxidative metabolism, while CDK4/6 inhibition resulted in increased metabolic function. Treatment with CDK4/6 inhibitors resulted in significantly increased mitochondrial mass and oxidative metabolism. Combination studies indicated that fulvestrant has a dominant effect on metabolism over CDK4/6 inhibitors, suggesting a novel basis for cooperation. Drug screening showed that both fulvestrant and CDK4/6 inhibitors limited the effectiveness of a host of conventional cytotoxic agents, yet are additive with multiple clinically employed targeted agents. Due to the enhanced metabolic flux in CDK4/6 arrested models, unique sensitivities to agents targeting metabolic functions were uncovered.

Conclusions: Dormant cells that have exited the cell cycle exhibit distinct metabolic features. These unique aspects of tumor biology can be targeted selectively using novel combinations in concert with endocrine therapy and/or CDK4/6 inhibitors.

Disclosure: All authors have declared no conflicts of interest.