Retinoblastoma protein (RB1)

The Retinoblastoma protein (pRb), encoded by the RB1 gene, is a fundamental tumor suppressor that acts as a gatekeeper for the G1/S phase transition of the cell cycle. It functions primarily by sequestering E2F transcription factors, thereby inhibiting the expression of genes necessary for DNA synthesis [UniProt P06400]. In a healthy cell, pRb is regulated by phosphorylation; however, in the vast majority of human cancers, the Rb pathway is inactivated through direct mutation, viral oncoprotein binding, or upstream signaling aberrations [PubMed: 25730344]. This pathway dysfunction is specifically exploited by ONCOS-102, an engineered oncolytic adenovirus (Ad5/3-D24-GMCSF). ONCOS-102 contains a 24-base pair deletion in the E1A region, which renders the virus unable to bind and inactivate pRb [Ranki et al., 2016, Gene Therapy]. Consequently, the virus cannot replicate in normal cells where pRb is active, but it replicates efficiently in cancer cells where the Rb pathway is already compromised and E2F is free. This mechanism provides a high degree of tumor selectivity, allowing the virus to induce oncolysis and stimulate a systemic anti-tumor immune response while sparing healthy tissue [Vassilev et al., 2015, Journal for ImmunoTherapy of Cancer].

Other names

pRbp105-RbRetinoblastoma-associated proteinRBRetinoblastoma 1PP105

ONCOS-102 exploits the loss of the Retinoblastoma pathway in cancer cells through a 24-base pair deletion (D24) in the E1A gene, which prevents the viral E1A protein from binding to and inactivating pRb. This restricts viral replication to cells where the Rb pathway is already defective and E2F transcription factors are constitutively active. Additionally, CDK4/6 inhibitors interact with this pathway by preventing the phosphorylation of pRb, thereby maintaining it in its active, growth-suppressive state.