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

Aslamuzzaman Kazi1, Liwei Chen1, Shengyan Xiang1

  • 1Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 21, 2021
PubMed
Abstract

Insights

Researchers uncovered that mutant KRas (mt KRas) cancer dependency is driven by cyclin-dependent kinases (CDKs). Inhibiting CDKs with AT7519 effectively treated KRas-dependent pancreatic cancer in preclinical models, suggesting potential for clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Mutant KRas (mt KRas) drives many human cancers, but not all are KRas-dependent.
  • The specific mechanisms underlying KRas dependency remain largely unknown.

Purpose of the Study:

  • To identify the molecular drivers of KRas dependency in human cancers.
  • To explore therapeutic strategies targeting KRas-dependent cancers.

Main Methods:

  • Global phosphoproteomics to analyze signaling networks.
  • Screening of FDA-approved drugs against cancer cell lines.
  • Genome-wide CRISPR/Cas9 viability screening to identify genetic vulnerabilities.

Main Results:

  • Phosphoproteomics identified a cyclin-dependent kinase (CDK) network as central to KRas dependency.
  • CRISPR/Cas9 analysis showed that inhibiting CDK1, CDK2, CDK7, or CDK9 was as effective as KRas knockout in pancreatic cancer cells.
  • The CDK inhibitor AT7519 induced apoptosis in mt KRas-dependent cells and suppressed tumor growth in patient-derived xenografts and organoid models.

Conclusions:

  • A direct link exists between CDK hyperactivation and mt KRas dependency.
  • Pharmacological inhibition of CDKs using AT7519 shows promise for treating mt KRas-driven pancreatic cancer.
  • Clinical investigation of AT7519 in patients with pancreatic cancer is warranted.

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