Targeting the AKT/cyclin D1 pathway to overcome intrinsic and acquired radioresistance of tumors for effective radiotherapy

Abstract

Purpose: Radiotherapy (RT) is a powerful tool in the treatment of cancer, having the advantage of preserving normal tissues. Clinical outcomes of RT are significantly improved by technological advances, enabling increased radiation doses directed very specifically to a tumor. However, tumor radioresistance remains a major impediment to effective RT. We have shown that human tumor cells surviving after repeated exposure to fractionated radiation (FR) of X-rays for 1 month have acquired radioresistance through constitutive activation of AKT and downstream cyclin D1 nuclear retention. Tumor radioresistance is also proposed to be an intrinsic characteristic of cancer stem cells (CSC), whose efficient DNA repair is thought to confer this phenotype. We have isolated radioresistant CD133-positive cells following exposure to long-term FR. These cells exhibited the CSC phenotype with activation of the AKT/cyclin D1 pathway. In this review, I summarize our current understanding of the molecular mechanisms underlying tumor radioresistance and propose a strategy for overcoming radioresistance by targeting the AKT/cyclin D1 pathway.

Conclusion: Two different mechanisms: acquired radioresistance of surviving tumor cells after RT and intrinsic radioresistance of CSC are associated with tumor radioresistance. Inhibition of the AKT pathway results in radiosensitization of both types of tumor radioresistance.

Keywords:

• AKT
• acquired radioresistance
• cancer stem cells
• cyclin D1
• radiotherapy

Acknowledgements

This review article summarizes the experiments carried out with the members of the Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University.

Disclosure statement

The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.

Additional information

Funding

The author was supported by a grant from the Japanese Ministry of Education and Science Houga (15K12220).