Nrf2 shapes response to lysosomal inhibition of radiation-induced senescent thyroid cancer cells

Therapy-induced senescence (TIS) is a potential outcome of anti-cancer treatments, characterized by a stable cell cycle arrest. However, it is now widely accepted that this process acts as a double-edged sword: in fact, senescent cells are active drivers of cancer relapse, aggressiveness and metastasis, through the release of pro-inflammatory factors and the ability to resume proliferation. Therefore, selectively targeting TIS cells, a strategy named one-two punch approach, is crucial to avoid their harmful effects. This may become particularly important for those aggressive tumors that currently lack effective therapeutic options, such as dedifferentiated thyroid tumors. To this purpose, identifying targetable characteristics of TIS cells is essential for the development of new senotherapeutics. TIS is often associated with variations of the autophagic flux, therefore, we investigated the interplay between autophagy and TIS in thyroid cancer cells, to explore a new potential target for senotherapy. We demonstrate that TIS thyroid cancer cells do not always exhibit a sufficient enlargement of the lysosomal compartment to maintain autophagy function. The deficiency in lysosomal biogenesis is driven by the inability of TFEB, the master regulator of this process, to properly enter and remain inside the nucleus. The disruption of the autophagic flux leads to the accumulation of SQSTM1/p62, which in turn activates the Nrf2 pathway. In contrast to cells with functional autophagy, Nrf2-activated cells display a higher tolerance to oxidative stress, making them resistant to the senolytic activity of lysosomal inhibitors.