ARK5 is an AMPK-related kinaseoften elevated inmetastatic colorectal cancers. ARK5 plays an important role in regulating metabolism in colorectal cancersand their ability to metastasis. This study explores the activity of ON 123300, a first in class dual kinase inhibitor targeting CDK4 and ARK5, in various colorectal cell lines.<br/><br/>We examined the effects of ON 123300 on RB and PI3K/AKT pathways in comparison with Palbociclib (PD 0332991) (a CDK4/6 inhibitor that does not have anti-ARK5 activity) in various colorectal cancer cell lines. Comparative analysis showed that ON 123300 and Palbociclib could effectively block CDK4/6 at similar concentrations, while ARK5 pathway was inhibited by ON 123300 only. ARK5 is also known to mediate metabolic changes in tumor cells. Treatment of ON 123300 in ARK5 expressing cells blocked glutamine uptake and ATP production. These metabolomic changes are not seen in cells treated with ON 123300 in non-ARK5expressing cells. These results demonstrate the specificityof ON 123300 to block metabolic changes mediated by ARK5.<br/><br/>We have developed a first in class dual inhibitor of CDK4 and ARK5 which can block proliferation and survival of metastatic colorectal cancers as a single agent. Using ON 123300, we could also blockmetabolomic changes in glutamine uptake and ATP production, and promote tumor cell apoptosis under the clinically relevant conditions. Thus, dual targeting strategy appears to be an effective approach for treating metastatic colorectal cancers.

Dual CDK4/ARK5 inhibition by ON 123300 for targeting metastatic colorectal cancer

2019 Fall National Meeting

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