Autophagy-targeted, senolytic therapy facilitates tumor relapse after oncogene inactivation

Although oncogene targeted therapy can delay tumor progression, the long-term outcome of these patients is often encountered by drug resistance and early tumor relapse. We analyzed the effects of oncogene inactivation in a transgenic cancer model on disease progression and identified the induction of senescence and the acquisition of polyploidy as two major factors that contribute to limited therapeutic success. Cancer cells, that became senescent after oncogene inactivation, were more susceptible to autophagy inhibition. However, the combination of oncogene inactivation and autophagy-targeted senolysis facilitated tumor relapse and led to a worse prognosis than oncogene inactivation itself. This study highlights the fact that drug candidate that show senolytic properties in vitro do not necessarily show senolytic effects in vivo as the therapeutic effect might be abrogated by non-senescence dependent features.