Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy

Abstract

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.

Figure 1.

Senescent cell as a target in one-two punch cancer therapy. A) Key knowledge gaps and future directions to advance one-two punch cancer therapy. B) Therapy-induced senescence (TIS) and one-two punch cancer therapy. Cancer therapies (first punch) induce senescence both in tumor and normal tissue. SnCs are normally cleared by immune surveillance but can accumulate after cancer therapy. Therapy-induced SnCs are heterogeneous and dynamic, which is also reflected in biomarkers, cellular plasticity, expression of SASPs and SCAPs, tissue of origin, and cell lineage. Selective clearance of SnCs with a serotherapeutic (second punch) in tumors will prevent tumor relapse, metastasis, and development of resistance to treatment. Similarly, selective clearance of SnCs in normal tissue in a spatiotemporal dynamic environment will prevent, mitigate, and treat therapy-induced side effects and restore tissue homeostasis. However, time of administration of the second punch therapy will be important to improve efficacy. The figure was created with BioRender.com. SnCs = senescent cells; SASP = senescence-associated secretory phenotype; SCAPs = senescent cell anti-apoptotic pathways.

Figure 2.

Schematic diagram of an approach to integrate one-two punch cancer therapy with personalized adaptive tumor therapy. To therapeutically exploit and benefit from the differences in response to treatment between tumor and normal tissue for the best patient outcome, factors that should be considered for pretreatment planning include tumor molecular profiling, tumor heterogeneity, imaging, identification of target(s), metabolic status, and planned integrated biomarkers for tumor diagnosis and treatment matching (136). Similar profiling of normal tissue response to treatment may include determination of genetic susceptibility, immune status, stromal tissue subsets, the impact of the anatomical location of the tumor on normal tissue, metabolic status, and biomarkers that predict response and adverse effects. In a one-two punch therapy, punch 1 may include spatially targeted radiotherapy (eg, dose-boost to hypoxic regions), molecularly targeted drugs, and/or immune therapy to the tumor, which will induce TIS in the tumor, stroma, and bystander tissue. Thus, tumor, stroma, and bystander tissue all need to be evaluated for TIS for the second punch to be successful. Biomarker-driven TIS evaluation will be essential to optimize immune modulation, dose, and schedule of the second punch with a suitable senolytic. Along with dynamic adaptive tumor targeting (with drugs, immune modulators, and radiation), the use of different types of senolytics may be necessary to address spatial, temporal, and tissue heterogeneity among tumors and senescent cells. Repeat treatment courses (punch #n) with senotherapeutics (senolytics or senomorphics) may be necessary to prevent tumor recurrence, drug resistance, plasticity, and normal tissue injury and mitigate and/or treat adverse effects months to years after completing the one-two punch therapy for optimal tissue remodeling and tissue function restoration. Dotted boxes represent current biomarkers and future opportunities to develop diagnostics or therapeutics for precision medicine in TIS. Tissues are indicated by the colors red (tumor), green (normal tissue), blue (stroma and immune related to tumor), and brown (bystander tissues). The figure was created with BioRender.com. Rx = prescription; TIS = therapy-induced senescence.