Loss of Retinoblastoma protein as a potential actionable event in cancer.


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Caterina Mancusi1,John Hartley2,Sibylle Mittnacht2
1Cancer Institute UCL,2Cancer Institute-UCL

Abstract

Background

Multiple tumour types including small cell lung cancer, glioblastoma and osteosarcoma show frequent loss of function mutations in the gene RB1. Retinoblastoma protein (RB1) is an important tumour suppressor, with broad roles in controlling cell growth and cell cycle progression. In addition, RB1 has complex functions that safeguard replicative and mitotic fidelity and DNA repair proficiency. Because of these latter roles of RB1, RB1-deficient tumours might be specifically dependent on functions that mitigate mitotic, replicative and DNA repair stresses. We therefore investigated the sensitivity of RB1-mutant cell lines towards DNA repair pathway inhibition.

Method

A panel of tumour cell lines differing in RB1 mutation status was assessed for sensitivity and response to DNA repair pathway inhibition using survival assays. Fate was analysed by live cell imaging and long-term colony formation assays.

Results

The work identifies substantive hypersensitivity of tumour cell lines deficient in functional RB1 towards inhibition of PARP and ATR and documents a mechanistic link of these observed sensitivities to the loss of RB1. The cellular and mechanistic basis underlying hypersensitivity of RB1 defective backgrounds to ATR inhibition was studied in more details.

Conclusion

These findings provide novel insight into the consequence of RB1 loss in cancers and point to opportunity for the rational design of improved therapies for tumours characterised by RB1 loss.