Will Increased Understanding of Cellular Senescence Lead to an End to Cancer?

Selective destruction of senescent cells in old tissues offers the promise of some degree of rejuvenation, coupled with effective therapies for a range of age-related diseases that currently cannot be controlled. In the past few years, a number of companies have raised venture funding for the development of senolytic therapies, those capable of removing some portion of senescent cells with an acceptable side-effect profile. The potential market is enormous, and thus despite the many potential competitors, any new mechanism by which senescent cells can be destroyed might be the pathway to success and revenue for the individuals and organizations involved in that research. A great deal more attention and funding is being devoted to the biochemistry of senescent cells than was the case even five years ago.

Cellular senescence is also of great interest to cancer researchers. Senescence in response to DNA damage is a way in which our biochemistry removes the riskiest cells from circulation. Senescence irreversibly shuts down the ability to replicate, senescent cells secrete signals to attract the immune system to the vicinity, so that problem cells can be destroyed, and in any case most senescent cells self-destruct shortly after entering this state. This works quite well at the outset, but not all senescent cells are destroyed. Eventually, there are enough of them that their signaling results in significant inflammation and disarray in the surrounding tissue - and that actually helps the development of cancer.

Nonetheless, at the front line of cancer research, any reliable approach that can force cancer cells into senescence is a win. Today's paper describes the possible foundation for such a treatment. While this isn't good for the patient in the long term - much of the shortened life expectancy of chemotherapy patients is most likely due to their high burden of senescent cells - it is a much better option than the outcome of uncontrolled cancer. It seems quite plausible that one of the results of the present raised level of interest in senescent cell biochemistry will be a range of more selective, more reliable, better ways to force cancer cells into senescence; approaches that rely on cellular biochemistry that is common to many or all cancers. That can then be coupled with senolytic therapies: turn the cancerous cells senescent and immediately destroy them. Might there be a practical end to cancer somewhere in the senescence research of the next decade or two? Maybe so.

Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function. Among the genes coding for the MYST family of KATs are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF). KAT6A has essential roles in normal haematopoietic stem cells and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers.

KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus, a function that requires its KAT activity. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer.

Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

In summary, using high-throughput screening followed by medicinal chemistry optimization, in-cell assays, biochemical assessment of target engagement, and tumour models in mice and fish, we have developed a novel class of inhibitors for a hitherto unexplored category of epigenetic regulators. These inhibitors engage the MYST family of lysine acetyltransferases in primary cells, specifically induce cell cycle exit and senescence, and are effective in preventing the progression of lymphoma in mice.