Journal Article

Radiotherapy alters expression of molecular targets in prostate cancer in a fractionation- and time-dependent manner

Aryankalayil, Molykutty J., Makinde, Adeola Y., Calvert, Valerie, Eke, Iris, Liotta, Lance, Bylicky, Michelle A., Coleman, C. Norman, Petricoin, Emanuel F., Graves, Edward E.

2022

Overview

The efficacy of molecular targeted therapy depends on expression and enzymatic activity of the target molecules. As radiotherapy modulates gene expression and protein phosphorylation dependent on dose and fractionation, we analyzed the long-term effects of irradiation on the post-radiation efficacy of molecular targeted drugs. We irradiated prostate cancer cells either with a single dose (SD) of 10 Gy x-ray or a multifractionated (MF) regimen with 10 fractions of 1 Gy. Whole genome arrays and reverse phase protein microarrays were used to determine gene expression and protein phosphorylation. Additionally, we evaluated radiation-induced pathway activation with the Ingenuity Pathway Analysis software. To measure cell survival and sensitivity to clinically used molecular targeted drugs, we performed colony formation assays. We found increased activation of several pathways regulating important cell functions such as cell migration and cell survival at 24 h after MF irradiation or at 2 months after SD irradiation. Further, cells which survived a SD of 10 Gy showed a long-term upregulation and increased activity of multiple molecular targets including AKT, IGF-1R, VEGFR2, or MET, while HDAC expression was decreased. In line with this, 10 Gy SD cells were more sensitive to target inhibition with Capivasertib or Ipatasertib (AKTi), BMS-754807 (IGF-1Ri), or Foretinib (VEGFR2/METi), but less sensitive to Panobinostat or Vorinostat (HDACi). In summary, understanding the molecular short- and long-term changes after irradiation can aid in optimizing the efficacy of multimodal radiation oncology in combination with post-irradiation molecularly-targeted drug treatment and improving the outcome of prostate cancer patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/80/304 / 631/80/458 / 631/80/82 / 631/80/86 / 692/699/67/1059/485 / 692/699/67/1059/602 / AKT protein / Cancer therapies / Cell migration / Cell Survival / DNA microarrays / Dose Fractionation, Radiation / Drug dosages / Enzymatic activity / Fractionation / Gene expression / Genomes / Histone deacetylase / Humanities and Social Sciences / Humans / Insulin-like growth factors / Irradiation / Kinases / Long-term effects / Male / multidisciplinary / Phosphorylation / Post-irradiation / Post-radiation / Prostate - metabolism / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - genetics / Prostatic Neoplasms - radiotherapy / Protein arrays / Proteins / Radiation Oncology / Radiation therapy / Science / Science (multidisciplinary)