A Precision Medicine Drug Discovery Pipeline Identifies Combined CDK2 and 9 Inhibition as a Novel Therapeutic Strategy in Colorectal Cancer.

Abstract

Colorectal cancer is the third most common cancer in the United States and responsible for over 50,000 deaths each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new treatments for this deadly disease. To address this need, we developed a precision medicine pipeline that integrates high-throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDX) to identify new treatments for colorectal cancer. High-throughput screens of 2,100 compounds were performed across six low-passage, patient-derived colorectal cancer cell lines. These screens identified the CDK inhibitor drug class among the most effective cytotoxic compounds across six colorectal cancer lines. Among this class, combined targeting of CDK1, 2, and 9 was the most effective, with IC50s ranging from 110 nmol/L to 1.2 μmol/L. Knockdown of CDK9 in the presence of a CDK2 inhibitor (CVT-313) showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Mechanistically, dual CDK2/9 inhibition induced significant G2-M arrest and anaphase catastrophe. Combined CDK2/9 inhibition in vivo synergistically reduced PDX tumor growth. Our precision medicine pipeline provides a robust screening and validation platform to identify promising new cancer therapies. Application of this platform to colorectal cancer pinpointed CDK2/9 dual inhibition as a novel combinatorial therapy to treat colorectal cancer.

• Authors: Jason A Somarelli, Roham Salman Roghani, Ali Sanjari Moghaddam, Beatrice C Thomas, Gabrielle Rupprecht, Kathryn E Ware, Erdem Altunel, John B Mantyh, So Young Kim, Shannon J McCall, Xiling Shen, Christopher R Mantyh, David S Hsu
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 12 Pg. 2516-2527 (12 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 33158998 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Protein Kinase Inhibitors
• CDK2 protein, human
• CDK9 protein, human
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 9

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Colorectal Neoplasms (diagnosis, etiology, metabolism)
• Cyclin-Dependent Kinase 2 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 9 (antagonists & inhibitors)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Discovery (methods)
• Drug Screening Assays, Antitumor (methods)
• Drug Synergism
• Female
• High-Throughput Screening Assays
• Humans
• Male
• Mice
• Mutation
• Precision Medicine (methods)
• Protein Kinase Inhibitors (pharmacology)
• Xenograft Model Antitumor Assays