Abstract
Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53-HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53-HDM2 inhibitors, such as NVP-CGM097.
Highlights
TP53 is a tumor suppressor gene that functions to prevent cancer by allowing cells to recover from various stress insults such as DNA damage or by triggering their elimination when the extent of the damage is beyond repair
NVP-CGM097 and NVP-CFC218 are substituted 1,2-dihydroisoquinolinone derivatives that were designed to mimic three key hydrophobic interactions made by p53 residues Phe19, Trp23, and Leu26 in the HDM2 pocket (Kussie et al, 1996; Garcıa-Echeverrıa et al, 2000; Furet et al, 2012) (Figure 1A)
The ability of NVP-CFC218 and NVP-CGM097 to disrupt the p53–HDM2 and p53–HDMX complexes was assessed in purified biochemical assays using time-resolved fluorescence resonance energy transfer (TR-FRET) to detect interactions between the N-terminal portion of HDM2 or HDMX and the human p53-derived peptide
Summary
TP53 is a tumor suppressor gene that functions to prevent cancer by allowing cells to recover from various stress insults such as DNA damage or by triggering their elimination when the extent of the damage is beyond repair. The p53 transcription factor acts in response to oncogenic or other stress signals to induce or repress a variety of target genes involved in cell cycle control, apoptosis, DNA repair, and cellular senescence (Vogelstein et al, 2000; Harris and Levine, 2005). The levels of p53 protein are tightly regulated by the E3 ubiquitin ligase HDM2 that targets p53 for ubiquitin-dependent proteasome degradation (Haupt et al, 1997; Kubbutat et al, 1997; Marine and Lozano, 2010).
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call