Resistance to Radiotherapy in Cancer

Abstract

Radiation therapy or radiotherapy is a medical treatment that uses high doses of ionizing radiation to eliminate cancer cells and shrink tumors. It works by targeting the DNA within the tumor cells restricting their proliferation. Radiotherapy has been used for treating cancer for more than 100 years. Along with surgery and chemotherapy, it is one of the three main and most common approaches used in cancer therapy. Nowadays, radiotherapy has become a standard treatment option for a wide range of cancers around the world, including lung, breast, cervical, and colorectal cancers. Around 50% of all patients will require radiotherapy, 60% of whom are treated with curative intent. Moreover, it is commonly used for palliative treatment. Radiotherapy provides 5-year local control and overall survival benefit in 10.4% and 2.4% of all cancer patients, respectively. The highest local control benefit is reported for cervical (33%), head and neck (32%), and prostate (26%) cancers. But no benefit is observed in pancreas, ovary, liver, kidney, and colon cancers. Such relatively low efficiency is related to the development of radiation resistance, which results in cancer recurrence, metastatic dissemination, and poor prognosis. The identification of radioresistance biomarkers allows for improving the treatment outcome. These biomarkers mainly include proteins involved in metabolism and cell signaling pathways.

Keywords: biomarkers; cancer; cellular metabolism; mitochondria; radioresistance; radiotherapy.

Figure 1

Molecular mechanisms of resistance to radiotherapy: TCA—tricarboxylic acid cycle; HIF1a—hypoxia-inducible factor 1-alpha; GLUT1—glucose transporter 1; ROS—reactive oxygen species; SOD—superoxide dismutase; TFs—transcription factors; MKP1—mitogen-activated protein kinase phosphatase-1; EGFR—epidermal growth factor receptor; VEGF—vascular endothelial growth factor; CDK—cyclin-dependent kinase; MDM2—mouse double minute 2 homolog. (A) Radiotherapy resistance and glycolysis: GLUT1 and PDK1 overexpression is associated with radiotherapy resistance. HIF1α upregulates pyruvate dehydrogenase kinase 1 (PDK1) expression. PDK1 phosphorylates and inactivates the PDH enzyme complex, which converts pyruvate to acetyl-coenzyme A, thus suppressing the tricarboxylic acid (TCA) cycle and decreasing the oxygen consumption rate. (B) Radiotherapy resistance and mitochondrial metabolism: MnSOD protects cells from ROS-induced damage and contributes to radiotherapy resistance. MKP1 limits the accumulation of phosphorylated JNK and, thus, prevents the induction of apoptosis. (C) Radiotherapy resistance and cell signaling pathways: MDM2 represses p53 transcriptional activity and contributes to radioresistance. P21 (a major target of p53) promotes cell cycle progression at the G1 phase in radioresistant cells. Survivin blocks the apoptotic pathway and enhances radiation resistance by inhibiting caspase 9. Figures were created in BioRender.