Dataset Information

Phosphoproteomics attributes aberrant signaling events to a druggable kinome in hepatocellular carcinom

ABSTRACT: To connect aberrant phospho-signaling events to therapeutic vulnerabilities in hepatocellular carcinoma (HCC), we performed a mass-spectrometry-based phosphoproteomic quantification of human HCC tumors, adjacent tissues and cell lines. We developed an integrated pipeline as the inference of druggable kinome (iDruKin), and computationally inferred differentially activated protein kinases from the phosphoproteomic data, and totally identified 16 kinases as potent drug targets in HCC. Together with experiments in cell lines, tissues and mice, our results not only confirmed MTOR as a major target in HCC, but also predicted the inhibition of CDK4/6 and the activation of PKCs and AMPKs to be promisingly effective in HCC therapy. Additionally, we observed most of these kinases are more significantly dysregulated in recurrent HCCs, and the kinase-activity signature was used to accurately classify HCC samples. Thus, this study demonstrated the potential of iDruKin in identifying drug targets and prognostic markers for HCC and other cancers.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ping Xu

PROVIDER: PXD023840 | iProX | Mon Jan 02 00:00:00 GMT 2023

REPOSITORIES: iProX

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Publications

Phosphoproteomics delineates hepatocellular carcinoma subtypes and pinpoints therapeutic targets.

Zhang Ze Z Zhang Zhenpeng Z Zhang Yao Y Li Yuan Y Li Kaixuan K Liu Shu S Cao Junning J Li Yanchang Y Peng Xuehui X Li Suzhen S Yin Yanan Y Jiang Songhao S Zuo Tao T Chang Lei L Xu Zhongwei Z Li Chonghui C Ding Jin J Wu Jushan J Zhang Wenwen W Wang Xinxin X Xia Guimin G Lu Shichun S Xu Ping P

Hepatology (Baltimore, Md.) 20250131 6

<h4>Background and aims</h4>Only a minority of patients could benefit from systemic therapy owing to the high heterogeneity of HCC. Therefore, a deeper understanding of the pathogenesis of HCC is essential for precision therapy. Genomic and proteomic studies of HCC have enhanced our understanding of HCC. However, the phosphoproteomic characterization of HCC remains poorly understood.<h4>Approach and results</h4>We conducted an in-depth analysis of a clinical cohort of HCC using high-coverage pho ...[more]

PMID: 39887258

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Project description:PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and arrayCGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort ovarian cancer patients. Concentration-dependent anti-proliferative effects of PD-0332991were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, Rb, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration and time dependent manner, and enhanced the effects of chemotherapy. Rb proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and associated with adverse clinical outcome (progression free survival, adjusted relative risk 1.49, 95%CI 0.99-2.22, p =0.054). PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. Gene expression of 40 individual ovarian cell lines relative to an ovarian cell line reference mix containing equal amounts of 41 ovarian cell lines (including OCC-1 which was later identified as originating from mouse). The expression data was correllated with cell line growth response to CDK 4/6 inhibitor PD-0332991 to identify genes associated with drug sensitivity and resistance.

Dataset Information

Phosphoproteomics attributes aberrant signaling events to a druggable kinome in hepatocellular carcinom

Publications

Phosphoproteomics delineates hepatocellular carcinoma subtypes and pinpoints therapeutic targets.

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