Figure 12. Proposed roles for cone precursor circuitry in retinoblastoma tumourigenesis and targeted therapy.

Signalling circuitry specific to maturing L/M-cone precursors is uniquely conducive to oncogenic transformation in response to pRB loss.^49,61,62 Specifically, these cone precursors express the transcription factors RXRγ and thyroid hormone receptor (TR) β2, and high levels of MYCN, MDM2, and pRB, and down regulate p27 via a SKP2-related mechanism. pRB depletion in maturing cone precursors blocks cone photoreceptor differentiation and enables proliferation and survival dependent upon MYCN, SKP2, and MDM2. Mouse models suggest that E2Fs and CDKs contribute to the proliferative response to pRB loss⁵⁹; these genes/proteins are also needed for proliferation and survival of human retinoblastoma cells.^61,207 Identifying the molecular mechanism mediating the cone precursor proliferative response to pRB loss provides opportunities to prevent tumor initiation, at least in preclinical models. Potential drugs are inhibitors of MYCN expression (JQ1),²⁰⁸ inhibitors of MDM2-mediated p53 degradation (Nutlin 3a),²⁰⁰ inhibitors of SKP2-mediated p27 degradation (C25),²⁰⁹ and inhibitors of E2F and CDK activities (HLM006474 and R547, respectively)⁵⁹. In addition, SYK was highly expressed in retinoblastoma but not normal retina.⁵³ Additional targeted agents may be effective against growing tumours, such as improved versions of the SYK inhibitor R406.^53,201