Senescence as biologic endpoint following pharmacological targeting of receptor tyrosine kinases in cancer.

Francica, Paola; Aebersold, Daniel; Medova, Michaela (2017). Senescence as biologic endpoint following pharmacological targeting of receptor tyrosine kinases in cancer. Biochemical pharmacology, 126, pp. 1-12. Elsevier 10.1016/j.bcp.2016.08.022

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Cellular senescence was first described in 1961 in a seminal study by Hayflick and Moorhead as a limit to the replicative lifespan of somatic cells after serial cultivation. Since then, major advances in our understanding of senescence have been achieved suggesting that this mechanism is activated also by oncogenic stimuli, oxidative stress and DNA damage, giving rise to the concept of premature senescence. Regardless of the initial trigger, numerous experimental observations have been provided to support the notion that both replicative and premature senescence play pivotal roles in early stages of tumorigenesis and in response of tumor cells to anticancer treatments. Moreover, various studies have suggested that the induction of senescence by both chemo- and radiotherapy in a variety of cancer types correlates with treatment outcome. As it is widely accepted that cellular senescence may function as a fundamental barrier of tumor progression, the significance of senescence for clinical interventions that make use of novel molecular targeting-based modalities needs to be well defined. Interestingly, despite numerous studies evaluating efficacies of receptor tyrosine kinases (RTKs) targeting strategies in both preclinical and clinical settings, the relevance of RTKs inhibition-associated senescence in tumors remains less characterized. Here we review the available literature that describes premature senescence as a major mechanism following targeting of RTKs in preclinical as well as in clinical settings. Additionally, we discuss the possible role of diverse RTKs in regulating the induction of senescence following cellular stress and possible implications of this crosstalk in identification of biomarkers of inhibitor-mediated chemo- and radiosensitization approaches.

Item Type:

Journal Article (Review Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Francica, Paola; Aebersold, Daniel and Medova, Michaela

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0006-2952

Publisher:

Elsevier

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

06 Apr 2017 12:50

Last Modified:

06 Apr 2017 12:50

Publisher DOI:

10.1016/j.bcp.2016.08.022

PubMed ID:

27574725

Uncontrolled Keywords:

Cancer; DNA damage response; Premature senescence; Receptor tyrosine kinases; Senescence induction; Targeted therapies

BORIS DOI:

10.7892/boris.92746

URI:

https://boris.unibe.ch/id/eprint/92746

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