Oncogene inactivation-induced senescence facilitates tumor relapse

Abstract

SUMMARYOncogene-targeted therapy has emerged as a promising avenue for delaying tumor progression. However, patients often develop drug resistance and early tumor recurrence. We analyzed the effects of oncogene inactivationin vitro, and identified the induction of senescence and metabolic reprogramming as two major adaptive mechanisms.In vivo, we observed that senescent cells exhibited an increased propensity for tumor relapse, accompanied by notable chromosomal abnormalities and the acquisition of alternative oncogenic pathways. Oncogene inactivation- induced senescence rendered cells reliant on autophagy, making them more susceptible to autophagy inhibitionin vitro. However, combining oncogene inactivation with autophagy-targeted senolysisin vivoin immunocompetent mice, unexpectedly facilitated tumor growth compared to oncogene inactivation alone. Similarly, oncogene inactivation in established tumors followed by autophagy inhibition led to increased tumor relapse in immunodeficient mice compared to the placebo group. Our results underscore senescence as a main mechanism allowing cancer cells to survive oncogene deprivation. Oncogene inactivation-induced senescence induces genetic abnormalities and is a main driver of tumor relapse. Our results suggest different metabolic dependencies of senescent cellsin vitroandin vivoand underscore the importance of evaluating potential drug candidates in relevant preclinical mouse models, as therapeutic effects observedin vitromay not necessarily translate to meaningful clinical outcomesin vivo.