Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation

Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells(1). This approach may help over come the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1,2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis(3-5). We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-17-92 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17-92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes.