Abstract
Mutations in Tp53 compromise therapeutic response, due either to the dominant-negative effect over the functional wild-type allele; or as a result of the survival advantage conferred by mutant p53 to which cancer cells become addicted. Thus, targeting mutant p53 represents an effective therapeutic strategy to treat over half of all cancers. We have therefore generated a series of small-interfering-RNAs, capable of targeting four p53 hot-spot mutants which represent ~20% of all p53 mutations. These mutant–p53-specific siRNAs (MupSi) are highly specific in silencing the expression of the intended mutants without affecting wild-type p53. Functionally, these MupSis induce cell death by abrogating both the addiction to mutant p53 and the dominant-negative effect; and retard tumor growth in xenografts when administered in a therapeutic setting. These data together demonstrate the possibility of targeting mutant p53 specifically to improve clinical outcome.
Highlights
A decade of pan-cancer genome sequencing efforts have resulted in the identification of a large number of genomic alterations across almost all cancer types [1, 2]
We embarked on generating Small-interfering RNAs (siRNA) that will be capable of only silencing the mutant p53 alleles, without having an impact on WT p53 expression
We generated a library of a large number of siRNAs, by performing sequence walks such that the position of the mutant nucleotide was varied with respect to the entire siRNA strand
Summary
A decade of pan-cancer genome sequencing efforts have resulted in the identification of a large number of genomic alterations across almost all cancer types [1, 2]. We demonstrate the generation of such mutant p53-specific siRNAs (referred to as MupSi), and demonstrate their ability in selectively silencing the expression of the intended mutant p53 forms, without cross-reactivity against other mutants or against the WT protein These siRNAs have been used to demonstrate the amelioration of the DN activity of mutant p53 over the WT form, thereby sensitizing tumor cells to therapeutic treatment. We show that these siRNAs can be used as therapeutic agents in patient-derived xenografts, and are capable of retarding tumor growth in vivo without resulting in any side effects or organ toxicity Together, these data demonstrate that mutation-specific siRNAs can be routinely generated, and this approach could be expanded to target the other major tumor suppressors and oncogenes that are altered in various pathological conditions
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