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As normal kidney tissue is relatively sensitive to radiation as opposed to the tumours that develop, it is believed that either genetic/proteomic or environmental changes occur in the process of transformation into RCC that renders the disease resistant to the effects of ionizing radiation. Hypothesized explanations:

1. **Hypoxia:**  Large part of tumor in RCC is in a state of hypoxia and hypoxia discourages indirect DNA damage as there is little oxygen available to form free radicals. This hypothesis is supported by the fact that the hypoxic response pathway is found activated in most RCC tumours via mutations in the VHL (Von Hippel-Lindau) gene which normally suppresses this pathway. As a result, genes that allow cells to cope with hypoxic conditions are up-regulated and the tumour survives whilst being resistant to both oxygen deprivation and radiation.

2. **Carbonic Anhydrase 9 (CA9):** Downstream product of the activated hypoxia pathway may be responsible for this resistance, namely carbonic anhydrase 9 (CA9 or CA IX) present in about 95% of the cases of RCC. While previously thought to merely catalyze the dissolution of CO2, it has been found to encourage growth,
invasion and metastasis in other tumour types, believed to be a result of increased acidification of the extracellular environment. The radiation resistance of two RCC cell lines 786-O (human CCRCC) and RAG (murine renal adenocarcinoma) was investigated by the clonogenic assay in the presence of a CA9  inhibitor or silencing RNA. The interference with CA9 by either of these methods significantly sensitizes 786-O cells to the effects of ionizing radiation in vitro.

Source: CA9 and Radiation Resistance in RCC - Daniel R. Gallino

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