Oncogene Withdrawal–Resistant PDAC Cells Require Mitochondrial Activity

Despite clinical success in targeting driver oncogenes in several cancers, recurrence rates indicate that a proportion of transformed cells escape therapeutic inhibition of oncogenic function. Pancreatic ductal adenocarcinoma (PDAC) remains a serious health concern, with a median survival of only six months, and is frequently characterized by mutation of KRAS; however, therapeutic targeting of mutant KRAS has proven difficult and the mechanisms that mediate PDAC relapse remain unclear. Viale, Pettazzoni, and colleagues assessed the role of mutant KRAS in PDAC maintenance, utilizing a conditional mouse model in which KRAS inactivation induced tumor regression that was followed by subsequent relapse. The small population of dormant surviving cells that remained after genetic or pharmacologic KRAS ablation re-entered the cell cycle and induced tumor relapse upon KRAS reconstitution both in vitro and in vivo, suggestive of differential KRAS addiction among subpopulations of PDAC cells. These surviving cells exhibited features of human pancreatic cancer stem cells and were enriched for tumor-initiating cells. Further analysis revealed that these surviving cells displayed a distinct metabolic profile, including increased mitochondrial mass, oxygen consumption, and reactive oxygen species production, indicative of enhanced mitochondrial electron transport chain (ETC) activity, and impaired glycolytic capacity. Consistent with the dependence of these cells on mitochondrial respiration and their inability to upregulate compensatory glycolytic metabolism, inhibition of oxidative phosphorylation (OXPHOS) selectively targeted surviving cells and synergized with KRAS inhibition to reduce spherogenic potential and delay tumor relapse. Mitochondrial ETC activity in surviving cells was dependent on autophagy and other catabolic processes such as microlipophagy, which promoted the survival of these cells and conferred resistance to environmental stress and nutrient deprivation. In sum, these data demonstrate that targeting OXPHOS in combination with oncogene inhibition may eliminate these dormant surviving cells and prevent PDAC relapse.

Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, Marchesini M, et al. Oncogene ablation–resistant pancreatic cancer cells depend on mitochondrial function. Nature 2014 Aug 10 [Epub ahead of print].