Boost Molecular-Targeted Mesothelioma Drugs by Reducing AKT1

The quest for novel ways of attacking mesothelioma took an interesting turn recently. Researchers from Europe and the Middle East found that tumor suppressor ERβ does not do its job in the presence of high levels of a particular enzyme.

The enzyme at issue is AKT1. As it so happens, mesothelioma patients typically have an overabundance of ATK1.

The researchers say their findings expand current knowledge in ways that may lead to new and better therapeutic strategies for malignant pleural mesothelioma.

The researchers are from the University of Piemonte Orientale in Novara, Italy; IRCCS San Martino in Genova, Italy; Sidra Medical and Research Center in Doha, Qatar; University of Leicester in the United Kingdom; and Karolinska Institutet in Huddinge, Sweden.

The title of their work — published in the journal Oncotarget — is “SIRT1 at the Crossroads of AKT1 and ERβ in Malignant Pleural Mesothelioma Cells.”

Poor Mesothelioma Prognosis Indicated by High AKT1 Levels

The researchers knew at the start of their investigation that malignant pleural mesothelioma patients have very poor prognoses if their tumors express high levels of AKT1.

AKT1 is one of three serine-threonine kinases that function as critical regulators of tumor cells. AKT1 determines if they survive or not, or if they remain in one location or spread.

When ATK1 activity increases, mesothelioma cells gain resistance to endocrine and molecular-targeted therapeutics. That appears to explain why those particular therapeutics often have limited effect.

The researchers say that AKT is generally activated in a multistep process that includes binding, translocation and phosphorylation.

There are 11 unique proteins that interact with AKT1. One of those is SIRT1. Among the effects SIRT1 can have on AKT1 is a biological change known as deacetylation.

The researchers indicated that AKT1 activity is inhibited if there is a loss of SIRT1-mediated deacetylation.

So reducing AKT1 activity would be a good strategy to make mesothelioma tumors less resistant to endocrine and molecular-targeted therapeutics, the researchers suggest.

And one potential way to reduce AKT1 activity would be to bring about a loss of SIRT1-mediated deacetylation.

Another way to inhibit AKT1 activity would be to increase tumor suppressor ERβ. It appears that ERβ creates an inhibitory feedback loop if activated by the selective agonist KB9520, the researchers report.

Mesothelioma Cells Become More Responsive to Treatment

The researchers came away from their investigation convinced that at the intersection of AKT1, SIRT1 and ERβ there may be found answers beneficial to mesothelioma patients.

In their article they discussed the ways in which SIRT1 facilitates “cross-talk” between AKT1 and ERβ in malignant pleural mesothelioma cells.

The researchers devoted a portion of their article to explaining the phenomenon of AKT1 isoform silencing in mesothelioma cells.

“Our data demonstrate that SIRT1 silencing increases AKT1 acetylation and suppresses aggressive properties of malignant pleural mesothelioma cells,” they wrote.

Interestingly, this silencing also appears responsible for causing biphasic mesothelioma cells to acquire characteristics more suggestive of the epithelioid type of mesothelioma cell.

This could be consequential because epithelioid mesothelioma cells are much more responsive to treatment than the biphasic type — which in turn are much more responsive to treatment than the sarcomatoid type.

Being able to encourage biphasic cells to become more like epithelioid mesothelioma cells would be a good thing indeed.