Adaptation of tumor cells to radiation therapy induces changes that are actionable by molecular targeted agents and immunotherapy. This report demonstrates that radiation-induced changes in integrin expression can be targeted two months later. Integrins are transmembrane cell adhesion molecules which are essential for cancer cell survival and proliferation. To analyze the short- and long-term effects of radiation on the integrin expression, prostate cancer cells (DU145, PC3, and LNCaP) were cultured in a 3D extracellular matrix and irradiated with either a single dose of radiation (2-10 Gy) or a multi-fractionated regimen (2-10 fractions of 1 Gy). Whole human genome microarrays, immunoblotting, immunoprecipitation assays, and immunofluorescence staining of integrins were performed. The results were confirmed in a prostate cancer xenograft model system. Interestingly, β1 and β4 integrins (ITGB1 and ITGB4) were upregulated after radiation in vitro and in vivo. This overexpression lasted for more than two months and was dose-dependent. Moreover, radiation-induced upregulation of β1 and β4 integrin resulted in significantly increased tumor cell death after treatment with inhibitory antibodies. Combined, these findings indicate that long-term tumor adaptation to radiation can result in an increased susceptibility of surviving cancer cells to molecular targeted therapy due to a radiation-induced overexpression of the target.
Radiation induces dose- and schedule-dependent adaptive changes that are targetable for an extended time; thus, suggesting radiotherapy as a unique strategy to orchestrate molecular processes thereby providing new radiation-drug treatment options within precision cancer medicine.
Molecular cancer research : MCR. 2018 Jul 24 [Epub ahead of print]
Iris Eke, Adeola Y Makinde, Molykutty J Aryankalayil, Jessica L Reedy, Deborah E Citrin, Sunita Chopra, Mansoor M Ahmed, C Norman Coleman
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health ., Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health., Radiation Oncology Branch, National Cancer Institute., Radiation Research Program (RRP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute, National Institutes of Health.