Targeting senescence as an anticancer therapy

Abstract

Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anticancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one-two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.

Keywords: cellular senescence; chemotherapy; oncogene-induced senescence; radiotherapy; senolytics; therapy-induced senescence.

Fig. 1

Strategies to target senescence in cancer (“one‐two punch”). Anti‐cancer therapy (first punch) induces the senescence of tumour cells. Conventional chemotherapy, radiotherapy and targeted therapies can be used to induce senescence. Induction of senescence in tumour cells unveils novel targetable vulnerabilities. Senolytic drugs can then be deployed to selectively target and kill senescent tumour cells (second punch). Several senolytic drugs have been described so far and their mechanisms of action are summarised here. Selective killing of senescent cancer cells will improve tumour control and regression. This “one‐two punch” approach to cancer therapy relies on the precise schedule of the administration of the sequential drug treatment to sensitise tumour to senolysis and restore tissue integrity. 17‐AAG, 17‐allylamino‐17‐demethoxygeldanamycin; 17‐DMAG, 17‐dimethylaminoethylamino‐17‐demethoxygeldanamycin; ac, acetylation; ADCC, antibody‐dependent cell‐mediated cytotoxicity; AURK, Aurora kinase; BET, bromodomain and extraterminal domain; CAR‐T cell, chimeric antigen receptor T cell; CDK, cyclin‐dependent kinase; DNMT, DNA methyltransferase; Doxo, doxorubicin; DRI, D‐retro inverso; gal‐NP, galactose‐nanoparticle; GMD, galactose‐modified duocarmycin; HDAC, histone deacetylase; HSP, heat shock protein; Nav, navitoclax; PARP, poly(ADP‐ribose) polymerase; PI3K, phosphatidylinositol tri‐phosphate; PLK, polo‐like kinase; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; uPAR, urokinase plasminogen activator receptor. Created with BioRender.com.