10780432ccr204781-sup-256946_2_figure_7022233_qqtczs.pptx (5.56 MB)
Supp Figures from Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer
figureposted 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
Joseph & Ann Matella Fund for Pancreatic Cancer Research
H. Lee Moffitt Cancer Center & Research Institute
ARTICLE ABSTRACTAmong 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.
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