High-Throughput Functional Genetic and Compound Screens Identify Targets for Senescence Induction in Cancer

Abstract

Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component SMARCB1 induces senescence in melanoma through strong activation of the MAP kinase pathway. From the compound screen, we identified multiple aurora kinase inhibitors as potent inducers of senescence in RAS mutant lung cancer. Senescent melanoma and lung cancer cells acquire sensitivity to the BCL2 family inhibitor ABT263. We propose a one-two punch approach for the treatment of cancer in which a drug is first used to induce senescence in cancer cells and a second drug is then used to kill senescent cancer cells.

Senescent cells: Living or dying is a matter of NK cells

“…[101][102][103] The idea of ameliorate aged tissue functionality by killing senescent cells is supported by different studies. [104][105][106] Anticancer prosenescence therapies are currently under investigation, 27,107,108 and recently approved drugs, such as CDK4/6 selective inhibitors, have been shown to induce tumor senescence. 25,26,109 Senescence induction in cancer cells may represent a valid approach to restrain tumor growth, but persistent senescent tumor cells may act as the silent factor for tumor relapse.…”

Anti‐cancer therapy: senescence is the new black

“…Such effects can potentially be countered by using a follow‐up therapy such as a senolytic agent: a drug that selectively kills senescent cells. We have recently shown the feasibility of such a “one‐two punch” consecutive therapy for cancer in which senescent cancer cells are killed by ABT‐263 (Wang et al , ), a selective inhibitor of the anti‐apoptotic BCL‐2, BCL‐W and BCL‐XL proteins (Chang et al , ; Zhu et al , ). It is also a possibility to further enhance the activity of recruited immune cells to senescent cancer cells by combining pro‐senescence therapy with a checkpoint immunotherapy.…”

Galactose-modified duocarmycin prodrugs as senolytics

“…Irradiation, chemotherapy and even some targeted anti-cancer drugs, all induce senescence (Schmitt et al 2002;Wang et al 2017). Although induction of tumour senescence explains the anti-cancer properties of these treatments, the generation of bystander senescent cells is responsible for their side effects .…”