A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal

Summary: VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) approved to treat multiple cancer types can promote metastatic disease in certain limited preclinical settings. Here, we show that stopping VEGFR TKI treatment after resistance can lead to rebound tumor growth that is driven by cellular changes resembling senescence-associated secretory phenotypes (SASPs) known to promote cancer progression. A SASP-mimicking antiangiogenic therapy-induced secretome (ATIS) was found to persist during short withdrawal periods, and blockade of known SASP regulators, including mTOR and IL-6, could blunt rebound effects. Critically, senescence hallmarks ultimately reversed after long drug withdrawal periods, suggesting that the transition to a permanent growth-arrested senescent state was incomplete and the hijacking of SASP machinery ultimately transient. These findings may account for the highly diverse and reversible cytokine changes observed in VEGF inhibitor-treated patients, and suggest senescence-targeted therapies (“senotherapeutics”)—particularly those that block SASP regulation—may improve outcomes in patients after VEGFR TKI failure. : Mastri et al. show that resistance to antiangiogenic therapy can induce senescence-mimicking secretory phenotypes that contribute to tumor promotion when treatment is stopped. Therapeutic targeting of senescence secretory regulators such as IL-6 and mTOR could improve outcomes after treatment failure. Keywords: antiangiogenic therapy, secretome, senescence, SASP, IL-6, mTOR, VEGF RTKI, resistance, metastasis, rebound