The inactivation of the tumour suppressor retinoblastoma-associated protein (RB) is considered a hallmark of cancer. In addition to deregulating proliferation, loss of RB function also increases apoptosis, and cells that lose RB become dependent on supporting pathways for their survival. A synthetic lethal approach exploits this dependence by targeting genes that are required for the survival of cells that lack RB function. Here (p. 2004), Wei Du and colleagues build on their previous work in flies, in which they found that the tuberous sclerosis complex 2 (TSC2) fly homologue gig induces synergistic cell death when rbf (the fly homologue of RB1) is lost; now, they investigate the mechanisms underlying this synthetic lethality. They show that the deletion of rbf together with either gig or tsc1 leads to an aberrant entry of mutant fly eye disc cells into S phase and increased levels of DNA double-strand breaks that contribute to cell death. In addition, they find that loss of rbf or tsc1 induces energy stress and sensitises cells to ATP depletion. Furthermore, rbf or tsc1 mutants depend on the metabolic regulator liver kinase B1 (LKB1) for their survival, as deletion of LKB1 results in increased cell death of rbf/tsc1 mutants. Taken together, these data point to multiple cellular stresses being induced and contributing to synthetic lethal interactions when RB and TSC1 or TSC2 are inactivated, which could be exploited for the treatment of tumours that have lost RB.

• © 2013. Published by The Company of Biologists Ltd