Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer

Abstract

Background:The phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is commonly deregulated in human cancer, hence many PI3K and mTOR inhibitors have been developed and have now reached clinical trials. Similarly, CDKs have been investigated as cancer drug targets.Methods:We have synthesised and characterised a series of 6-aminopyrimidines identified from a kinase screen that inhibit PI3K and/or mTOR and/or CDK2. Kinase inhibition, tumour cell growth, cell cycle distribution, cytotoxicity and signalling experiments were undertaken in HCT116 and HT29 colorectal cancer cell lines, and in vivo HT29 efficacy studies.Results:2,6-Diaminopyrimidines with an O4-cyclohexylmethyl substituent and a C-5-nitroso or cyano group (1,2,5) induced cell cycle phase alterations and were growth inhibitory (GI50<20 μM). Compound 1, but not 2 or 5, potently inhibits CDK2 (IC50=0.1 nM) as well as PI3K, and was cytotoxic at growth inhibitory concentrations. Consistent with kinase inhibition data, compound 1 reduced phospho-Rb and phospho-rS6 at GI50 concentrations. Combination of NU6102 (CDK2 inhibitor) and pictilisib (GDC-0941; pan-PI3K inhibitor) resulted in synergistic growth inhibition, and enhanced cytotoxicity in HT29 cells in vitro and HT29 tumour growth inhibition in vivo.Conclusions:These studies identified a novel series of mixed CDK2/PI3K inhibitors and demonstrate that dual targeting of CDK2 and PI3K can result in enhanced antitumour activity.

Involvement of PI3K/Akt pathway in the protective effect of hesperidin against a chemically induced liver cancer in rats

“…CDK2 was upregulated in DEN‐induced HCC to increase the proliferation of dysplastic hepatocytes and hence its inhibition exhibited an anti‐HCC effect . Additionally, CDK2 is a downstream target of the PI3K/Akt pathway and the dual targeting of PI3K and CDK2 was found to be a chemopreventive and therapeutic strategy for colorectal, breast, and prostate cancers . Moreover, hesperidin was found to inhibit the proliferation of cervical cancer cells by CDK2 downregulation, which is consistent with our findings …”

Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy

“…In recent years, a number of CDK2 inhibitors have been developed and are under clinical evaluation [16]. Recently, several strategies have been integrated to develop different classes of inhibitors for CDK2 to control glioma and colorectal cancers [17]. Still, the available inhibitors of CDK2 are not selective and possess on-and off-target effects.…”

Circular RNAs: A novel type of biomarker and genetic tools in cancer

“…CDK2 could interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21 could inhibit these interactions and arrest cell cycle progression [ 76 ]. As CDK2 is associated with multiple cancers, like breast cancer [ 77 ], colorectal cancer [ 78 ], non-small cell lung cancer (NSCLC) [ 79 ], hence, circ-Foxo3 also carry out functions in cancers above by forming circ-Foxo3-p21-CDK2 ternary complex. What's more, circ-Foxo3 can also bind to proteins ID1, E2F1, FAK, and HIF-1α, retaining them in the cytoplasm and promoting cardiac senescence [ 76 ].…”