Spontaneous Genomic Alterations in a Chimeric Model of Colorectal Cancer Enable Metastasis and Guide Effective Combinatorial Therapy

Abstract

Colon cancer is the second most common cause of cancer mortality in the Western world with metastasis commonly present at the time of diagnosis. Screening for propagation and metastatic behavior in a novel chimeric-mouse colon cancer model, driven by mutant p53 and β-Catenin, led to the identification of a unique, invasive adenocarcinoma. Comparison of the genome of this tumor, CB42, with genomes from non-propagating tumors by array CGH and sequencing revealed an amplicon on chromosome five containing CDK6 and CDK14, and a KRAS mutation, respectively. Single agent small molecule inhibition of either CDK6 or MEK, a kinase downstream of KRAS, led to tumor growth inhibition in vivo whereas combination therapy not only led to regression of the subcutaneous tumors, but also near complete inhibition of lung metastasis; thus, genomic analysis of this tumor led to effective, individualized treatment.

Protein Kinase A–Mediated Effects of Protein Kinase C Partial Agonist 5-(Hydroxymethyl)Isophthalate 1a3 in Colorectal Cancer Cells

“…Calcium/calmodulin-dependent protein kinase type 2 (CaMK 2) (Chen et al, 2017) and cyclin-dependent kinase 14 (CDK14) (Zhou et al, 2014) have been shown to be overexpressed in human colon cancer and contribute to invasiveness. The most upregulated kinases were different after 2 hours compared to 30 minutes (Table 2, Supplementary Figure S4) and there was no clear correlation or trend between the time points.…”

Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity

“…An example of such a subfamily of kinases is the TAIRE CDKs, which include CDK14-CDK18. Although genetic studies have implicated CDK14 and CDK16 as therapeutic targets, especially in the context of colorectal cancers (Zhang et al, 2016b;Zhu et al, 2016;Zhou et al, 2014), not much is known about their biological roles and substrate preferences.…”

“…CDK14 (also annotated as PFTAIRE1 and PFTK) is overexpressed in human colorectal cancer patients, relative to surrounding normal colorectal lesions, and is associated with poor prognosis (Zhang et al, 2016b). CDK14 is also spontaneously amplified in a chimericmouse colon cancer model driven by mutant p53 and b-catenin (Zhou et al, 2014). Knockdown of CDK16 reportedly causes mild inhibition of HCT116 colorectal cancer cell growth (Yanagi et al, 2016).…”

Genetic and pharmacological reduction of CDK14 mitigates α-synuclein pathology in human neurons and in rodent models of Parkinson’s disease

“…CDK14 is a brain expressed protein kinase with a largely unknown biological function ( 23 ). Its expression is upregulated in certain cancers, such as esophageal and colorectal cancer, for which it has generated attention as a therapeutic target ( 24 , 25 ). In fact, this has led to the recent development of FMF-04-159-2, a potent, covalent inhibitor of CDK14 ( 26 ).…”