Senolytics as a Potential Treatment for Precancerous Lesions

It is reasonable to think that intermittent treatment with senolytics can suppress cancer incidence by killing the senescent cells that are present in precancerous lesions, whether or not they are too small to be identified by present screening techniques. This should reduce the number of cells that can potentially go on to become cancerous, and also remove the contribution of senescent cell signaling to the growth and inflammatory status of the lesion. It should not be too challenging to prove this hypothesis in animal models, but prevention of cancer in the general sense is, unfortunately, a hard sell when it comes to clinical development. It is slow and expensive to run clinical trials for five or more years with cancer prevention in mind, and few organizations or investors would choose to take on that cost.

Senescence is a cell state that contributes to several homeostatic and pathological processes. In addition to being induced in somatic cells in response to replicative exhaustion (replicative senescence, RS) as part of organismal aging, senescence can also be triggered prematurely by oncogene hyperactivation or tumor suppressor dysfunction (oncogene-induced senescence, OIS). Consequently, senescent cells comprise a major component of precancerous lesions of skin, oral mucosa, nasopharynx, prostate, gut, and lung.

Unfortunately, invasive (or minimally invasive) interventions are currently the only available approach employed to eradicate premalignant lesions that carry the potential for cancer progression. Oncogene-Induced Senescence (OIS) is one form of senescence that occurs in response to oncogene overexpression in somatic cells and is present in precancerous lesions. While the contribution of OIS to disease progression is undetermined, recent evidence suggests that senescent cells are permissive for malignant transformation.

Senolytics are a newly emerging drug class capable of selectively eliminating senescent cells. While senolytics have been successfully demonstrated to mitigate a myriad of aging-related pathologies and to cull senescent cancer cells, there is a paucity of evidence for the potential use of senolytics as a novel approach to eliminate oncogene-induced senescent cells. This commentary will: (i) summarize evidence in established models of OIS including B-Raf-induced nevi, transgenic lung cancer, and pancreatic adenocarcinoma models as well as evidence from clinical precancerous lesions; (ii) suggest that OIS is targetable; and (iii) propose the utilization of senolytic agents as a revolutionary means to interfere with the ability of senescent premalignant cells to progress to cancer in vitro and in vivo. If proven to be effective, senolytics will represent an emerging tool to pharmacologically treat precancerous lesions.


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