Radiation-induced senescence : a possible mechanism of resistance and a tumour-promoting pathway in NSCLC

Radiotherapy is a common treatment modality for NSCLC which despite continuing advances in the field still presents very high rates of recurrence, with secondary tumours typically more difficult to treat, due in part to the radioresistance of these tumour's cells. This ultimately leads to poor treatment outcomes. One contributing factor may be the induction of senescence, a form of permanent cell cycle arrest, following radiotherapy treatment. While senescence is initially considered beneficial to the outcome of radiotherapy, an accumulation of senescent cells is known to disrupt tissue homeostasis and even favour the growth and survival of cancer cells. Therefore, the use of senolytics in combination with radiotherapy could greatly benefit NSCLC patients. Thus far use of such drugs has not been possible as there are no targetable markers of senescence specific enough to prevent damage to other cell types. The relative radiosensitivity of a panel of four NSCLC cell lines was assessed following different doses of ionising radiation (IR) and then investigated for the presence of senescence under the same conditions. This showed a correlation between radioresistance and the cells' ability to induce senescence following radiation. The senescence associated secretory phenotype (SASP) of the panel was analysed using shotgun proteomics to search for the presence of novel markers of senescence. Several interesting candidates were found which could present better targets for novel senolytics. The effects of these SASP on other cells were also tested, which showed increases in wound healing activity and invasion, indicating that the secretome of senescent cells had pro-proliferative activity on neighbouring cells. Our results demonstrate that clinically relevant doses of IR induce senescence in NSCLC cells and that their SASP can affect surrounding cells. We propose that the presence of senescent cells post IR treatment may be leading to high rates of radiotherapy failure and recurrence.