Poster Presentation 25th Lorne Cancer Conference 2013

Bioenergetic modulation sensitises acute lymphoblastic leukaemia to glucocorticoids (#339)

Amy L Samuels 1 2 , Jasmin Heng 1 , Ferrer Ong 1 , Alex H Beesley 1 2 , Ursula R Kees 1 2
  1. Telethon Institute for Child Health Research, Subiaco, WA, Australia
  2. Centre for Child Health Research, The University of Western Australia, Perth, Western Australia
Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in children. Despite significant improvements in the treatment of childhood T-cell ALL (T-ALL), as many as 30% of patients relapse and face a dismal prognosis. Resistance to glucocorticoids (GC) is known to be a major factor contributing to the poor prognosis of relapsed T-ALL. However, the mechanisms involved in GC resistance are poorly understood. Utilising a unique panel of GC-resistant and sensitive T-ALL cell lines we performed gene expression profiling to investigate molecular changes underpinning the resistant phenotype. These studies revealed distinct differences between resistant and sensitive T-ALL cell lines. Gene set enrichment analysis (GSEA) associated cellular metabolism pathways including glycolysis, oxidative phosphorylation and cholesterol biosynthesis, with GC resistance. Combined use of the GC methylprednisolone (Mpred) and the oxidative phosphorylation inhibitor oligomycin was able to overcome GC resistance in vitro, as was the combination of Mpred and the cholesterol synthesis inhibitor simvastatin. Our results indicate that T-ALL cells are able to switch between bioenergetic pathways in response to cellular cues such as nutrient and pharmacological exposure, and that concomitant inhibition of multiple components of cellular energy pathways is a promising treatment strategy to overcome GC-resistance in T-ALL cells