Use of senotherapies to decrease radiation-induced senescence and resistance in lung cancer.

Lung cancer is the principal cause of oncogenic mortality, non-small cell lung cancer (NSCLC) being the most common form. Although different treatments are available, including radiation therapy, NSCLC usually relapse. Radiotherapy has been shown to induce senescent cells, which may contribute to this relapse. This could be reduced targeting senescent cells with senotherapies. We studied the response of different NSCLC cell lines to radiation. We found that wild type p53 cells were more prone to go into senescence and show resistance to radiation than mutant p53 cells. The secretion profile of these cells and its effect on cell motility was also proportional to the presence of senescent cells. Moreover, a mass spectrometry screen identified an heterogenous cell-specific secretory phenotype linked to senescence. This supports the therapeutic potential of preventing senescent cell accumulation after radiotherapy. To this end, we studied the effect of senolytics (drugs that specifically kill senescent cells) and senoblockers (which prevent senescence). The results depended on the cell type but successfully achieve the goals in different settings. Finally, we obtained a list of radiation-induced senescence markers using a proteomics approach, which could help predict which patients could benefit from senotherapies as adjuvants to radiotherapy. Our data together suggest that senotherapies (senolytics and/or senoblockers) could minimise the accumulation of senescent cells after radiotherapy and thus reduce chances of relapse, and provide a rationale to stratify patients according to the ability of cancer cells to enter senescence.