American Association for Cancer Research
Browse

Supp Figures from Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer

Download (5.56 MB)
figure
posted on 2023-03-31, 22:44 authored by Aslamuzzaman Kazi, Liwei Chen, Shengyan Xiang, Rajanikanth Vangipurapu, Hua Yang, Francisca Beato, Bin Fang, Terence M. Williams, Kazim Husain, Patrick Underwood, Jason B. Fleming, Mokenge Malafa, Eric A. Welsh, John Koomen, José Trevino, Saïd M. Sebti

Supplementary Figures

Funding

NIH

Joseph & Ann Matella Fund for Pancreatic Cancer Research

H. Lee Moffitt Cancer Center & Research Institute

NCI

History

ARTICLE ABSTRACT

Among human cancers that harbor mutant (mt) KRas, some, but not all, are dependent on mt KRas. However, little is known about what drives KRas dependency. Global phosphoproteomics, screening of a chemical library of FDA drugs, and genome-wide CRISPR/Cas9 viability database analysis were used to identify vulnerabilities of KRas dependency. Global phosphoproteomics revealed that KRas dependency is driven by a cyclin-dependent kinase (CDK) network. CRISPR/Cas9 viability database analysis revealed that, in mt KRas-driven pancreatic cancer cells, knocking out the cell-cycle regulators CDK1 or CDK2 or the transcriptional regulators CDK7 or CDK9 was as effective as knocking out KRas. Furthermore, screening of a library of FDA drugs identified AT7519, a CDK1, 2, 7, and 9 inhibitor, as a potent inducer of apoptosis in mt KRas-dependent, but not in mt KRas-independent, human cancer cells. In vivo AT7519 inhibited the phosphorylation of CDK1, 2, 7, and 9 substrates and suppressed growth of xenografts from 5 patients with pancreatic cancer. AT7519 also abrogated mt KRas and mt p53 primary and metastatic pancreatic cancer in three-dimensional (3D) organoids from 2 patients, 3D cocultures from 8 patients, and mouse 3D organoids from pancreatic intraepithelial neoplasia, primary, and metastatic tumors. A link between CDK hyperactivation and mt KRas dependency was uncovered and pharmacologically exploited to abrogate mt KRas-driven pancreatic cancer in highly relevant models, warranting clinical investigations of AT7519 in patients with pancreatic cancer.

Usage metrics

    Clinical Cancer Research

    Categories

    Keywords

    Cell SignalingGuanine nucleotide binding proteins and effectorsProtein serine-threonine kinasesDrug TargetsOncoprotein & tumor suppressor drug targetsProtein kinase & phosphatase drug targetsGastrointestinal CancersPancreatic cancerPreclinical ModelsAnimal models of cancerProteomicsSmall Molecule AgentsKinase inhibitors

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC