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.

Cyclin-Dependent Kinase Inhibitors and Their Therapeutic Potential in Colorectal Cancer Treatment

“…This effect was dependent on the duration of the treatment, since more E3F/Rb complexes were observed after 48 h than after 24 h in HT29 cell line. Inhibition of CDK2 in patient-derived human cell lines using CVT-313 has minimal effect on cell death ( Somarelli et al, 2020 ). Nevertheless, combined therapy using CDK2 and 9 inhibitors significantly increased the numbers of cells arrested in G2/M.…”

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

“…Recently, CDK family molecules have been used as novel molecular markers for tumor-targeted therapy. As a star molecule, CDK2 ( Kawakami et al, 2020 ) participates in classic pathways in various cancers, such as colorectal cancer ( Somarelli et al, 2020 ), neuroblastoma ( Poon et al, 2020 ), breast cancer ( Hur et al, 2020 ), hepatocellular carcinoma ( Hou et al, 2019 ), and prostate cancer ( Washino et al, 2019 ). However, there are few studies on the mechanism of CDK2 in lung cancer.…”

Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development

“…CDK inhibitors show promising activity in CRC with combined targeting of CDK1, 2, and 9 considered the most effective strategy. 37 …”

“…CDK inhibitors show promising activity in CRC with combined targeting of CDK1, 2, and 9 considered the most effective strategy. 37 Activation of the PI3K/Akt pathway, which is frequently mutated in CRC with enrichment in mCRC, 10 also confers resistance to anti-EGFR therapy and to first-line chemotherapy. 38 While multiple clinical trials have evaluated Akt inhibition, Akt-targeted therapies directed in general have not been effective for mCRC treatment.…”