Promotion of tumor cell senescence by the antibody-drug conjugate, sacituzumab govitecan.

Sacituzumab govitecan (SG), an antibody-drug conjugate approved for the treatment of triple-negative breast cancer and hormone receptor-positive breast cancer, is currently undergoing clinical trials in multiple forms of cancer. However, there is currently no preclinical information relating to whether senescence is one component of the response to this antibody-drug conjugate in tumor cells. Our studies provide evidence for senescence in response to SG (β-galactosidase staining with quantification by flow cytometry, upregulation of p21 and downregulation of Lamin B1, and expression of interleukins IL-6, IL-8, and IL-1β) in 9 tumor cell lines derived from breast, prostate, lung, ovarian, and colorectal cancer. Senescence induction was associated with a transient growth arrest followed by proliferative recovery. Similar results were generated using SN-38, the toxic payload that is released from SG. We conclude that one central component of the tumor cell response to SG is a transient senescence-associated growth arrest that can generate a pool of surviving tumor cells with the potential to contribute to disease recurrence. SIGNIFICANCE STATEMENT: Antibody-drug conjugates (ADCs) are among the newest anticancer therapies. Current studies demonstrate, for the first time, that one component of the response to an ADC, sacituzumab govitecan, is the promotion of senescence. This raises the possibility that the inclusion of senolytics or senomorphics in combination with ADCs could improve their clinical effectiveness and interfere with disease recurrence.