634 Depletion of senescent cells improves targeted therapy outcome in melanoma

Cellular senescence is a non-proliferative but viable state that can be induced by oncogene expression and anti-cancer therapeutics, such as BRAF inhibition, has long been considered beneficial tumor suppressive mechanism. However, senescent cells express well-characterized senescence-associated secretory phenotype (SASP), which may contribute to an immunosuppressive microenvironment increased malignant phenotype, leading recurrence metastasis. To investigate the role of in growth, we treated B1610 (B16) melanoma vitro with senolytic drug ABT737 or vehicle control injected 5x104 into syngeneic mice. We found pre-treated B16 grew significantly smaller tumors compared controls. Tumors from senolytic-treated had fewer β-galactosidase p16 expressing cells, correlated decreased SASP expression, reduced infiltration myeloid-derived suppressor cells. next mutant human inhibitor PLX4720, significant increase number members IL-1β, IL-6, IL-8, phenomenon known therapy-induced senescence. Further, there was apoptotic when combination PLX4720 ABT737, suggesting this more effective for eradication than inhibition alone. then asked whether eliminating drugs enhanced therapy. YUMM1.7 subcutaneous ABT263 showed durable repression regrowth Our findings suggest potential mechanism acquired resistance evasion anti-tumor immune responses, overcome depleting drugs.