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• W2567607965 abstract "Palbociclib (PD0332991) is a cyclin dependent kinase 4 and 6 inhibitor being developed for treatment of breast cancer. In order to evaluate the kinome-wide impacts of Palbociclib in an in-vivo setting, nude mice inoculated with COLO-205 (human colon carcinoma) cells were administered Palbociclib at different doses (12.5, 75 and 150mg/kg once daily for 3 days. Tumors were collected at various time points after the final dose (1, 3, 6, 12, 24 & 48 hours), lysed and subjected to in-situ kinase profiling using the KinativTM technology. Tumor lysates were probed with an ATP acylphosphate desthiobiotin probe which covalently modifies lysine residues in the kinase active site. Samples are then denatured, trypsinized, and the probe-labeled peptides captured with streptavidin, eluted, and quantitated by targeted mass spectrometry. The presence of an inhibitor bound to the active site of a kinase prevents the probe binding, resulting in the loss of MS signal for peptides from that kinase. In addition, the upregulation or downregulation of kinase proteins can also result in changes in the MS signals in palbociclib versus vehicle-treated samples. A total of 180 kinases were quantified. As expected, direct targets of palbociclib were observed to be inhibited in this study (i.e., kinases inhibited by Palbociclib in Colo205 lysate), including CDK4 &6 as well as ERK5, JNK, CDK16 &17, PIK3C3 and PIP4K2C. The observed inhibition of these targets was both dose and time dependent. Significantly, the MS signals for additional kinases not observed to directly bind Palbociclib in Colo205 lysate were also strongly downregulated in this study. These include CDC2, AurA, AurB, PLK1 and MASTL; kinases critical for cell cycle progression. We hypothesize that the downregulation of these kinases was due to cell cycle arrest in G1 phase. Consistent with this hypothesis, the downregulation of these kinases corresponded well with the inhibition of phosphorylated (Ser780; pRb) as demonstrated by Western Blots of a part of tumor tissue used for the Kinome profiling. Taken together, these results highlight the utility of kinome wide profiling in tumor samples collected from xenograft mice to better understand both pharmacodynamics of target engagement as well as pathway effects elicited by compound treatment. Citation Format: Geeta Sharma, Subha Vogeti, Wendy Grant, Shuzhen Wu, Christa Dias, Tyzoon Nomanbhoy, Jiangyue Wu, Arwin Aban. In-situ Kinome wide profiling of Palbociclib treated COLO-205 human tumor xenograft samples. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3092. doi:10.1158/1538-7445.AM2015-3092" @default.
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• W2567607965 date "2015-08-01" @default.
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• W2567607965 title "Abstract 3092: In-situ Kinome wide profiling of Palbociclib treated COLO-205 human tumor xenograft samples" @default.
• W2567607965 doi "https://doi.org/10.1158/1538-7445.am2015-3092" @default.
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