Researchers from the Walter and Eliza Hall Institute, the Monash Institute of Pharmaceutical Sciences, and Cancer Therapeutics CRC have developed a new type of drug that harnesses cellular senescence as a weapon against cancer [1].

Study abstract Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function. Among the genes coding for the MYST family of KATs (KAT5–KAT8) 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.

Old and new approaches

Historically, doctors attempted to eliminate cancer by causing cancer cells permanent, irreparable damage. By administering chemotherapeutics or irradiating the patient, they would inflict damage to the DNA of cancer cells, resulting in their death and thus preventing the tumor from spreading further.

The problem with this approach is that it cannot be precisely targeted to cancer cells; inevitably, the DNA of healthy cells is damaged as well, leading to short-term side effects, such as hair loss, fatigue, weakening of the immune system, and even the possibility of trading one cancer for another, as, in the long term, the damage inflicted to healthy cells might cause them to turn cancerous.

More sophisticated approaches involve, for example, immunotherapy—turning the immune system specifically against cancer cells—but the authors of this study proved that it’s possible to turn one of the hallmarks of aging—cellular senescence—against cancer.







The new method

Genes coding for the KAT6A and KAT6B proteins have been implicated as important drivers of cancer; KAT6A, in particular, is known to suppress senescence, a state of arrested growth in which cells don’t die but are unable to replicate themselves.

In animal models of lymphoma, inhibition of these genes led to impressive lifespan gains; thus, the researchers began searching for ways to pharmacologically suppress the corresponding proteins. The drugs they have used proved safe in animal models, arresting tumor growth by turning cells senescent while leaving alone healthy ones; as they do not act by damaging DNA, they don’t cause the same side effects of radiotherapy or chemotherapy. The drugs are not ready yet for human use, but the researchers believe that they might one day prove useful to prevent cancer from recurring.

This achievement is even more impressive considering that, until now, it was thought to be impossible to design drugs that intervene in these genes. Indeed, it has taken nearly a decade of collaborative efforts from several researchers to develop these inhibitors; the same team is now looking to turn the compounds into a version that can be used in human trials.

A potential catch







Cellular senescence is thought to be a mechanism for protection against cancer; however, lingering senescent cells in the body have been associated with a number of age-related pathologies, including cancer itself. Normally, these cells are eliminated by the immune system, but, as we age, this clearing process becomes less effective. For this reason, drugs that eliminate senescent cells are currently being designed and tested, even in humans, to prevent age-related diseases.

Senescent cells are not good to have in your body, but they are not nearly as dangerous as cancer cells, so turning cancer cells senescent is a pretty good trade-off. We look forward to seeing how this new potential therapy will evolve.

Literature

[1] Jonathan B. Baell et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature (2018).





