Gene Signature Identified in Mechanism of Resistance to Cancer Drug Therapy

In cancer drug therapy, it has been found that cancer cells develop resistance to proteasome inhibitors which limits their use as cancer drugs. A research team from the Whitehead Institute has now identified ways by which such resistance is developed, by studying mechanisms used by various types of cancer cells. The understanding of such mechanisms will highlight vulnerabilities of these cancer cells providing scope for a more targeted therapy. The study published in the Journal Proceedings of The National Academy of Sciences titled “Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers” also aided in identifying a biomarker that can be used to understand the proteasome inhibitor state of the immune cells.

The proteasome is a multi-unit enzyme complex, which plays a key role in regulation of the proteins that are involved in cell-cycle progression as well as in apoptosis (programmed cell death). Therefore, they are found to be important targets for anti-cancer therapy. The degradation of protein is a complex pathway that follows distinct pathways, with the ubiquitin proteasome pathway (UPP) being the most significant. Nearly 80% of the proteins are degraded via this pathway.

Proteasome Inhibitors

These inhibitors were once developed as in vitro probes to understand the function of proteasome’s catalytic activity. These studies aided in understanding the important role of proteasome in cell function and the possible use of proteasome inhibitors in cancer therapeutics. Previous studies have shown that proteasome inhibitors were involved in apoptosis in leukemic cell lines and in Burkitt lymphoma, were found to be very active, highlighting their importance in cancer disease progression.

There were many in-vitro studies conducted and these proteasome inhibitors found that they had a broad spectrum

• Anti-proliferative
• Pro-apoptotic activity

against both solid tumors as well as hematological tumors. These studies showed that proteasome inhibitors could be used in the treatment of cancer but the compounds that were available were not very potent initially. However, newer inhibitors were found to have great potency against cancer cells, but they have recent study show a development of resistance to these inhibitors.

The lead study author, Dr. Peter Tsvetkov who is a postgraduate doctor at the Whitehead Institute said that the team of researchers from The Whitehead Institute identified a counterintuitive process by which the cancer cells developed resistance to proteasome inhibitors. The mechanism that was identified by these researchers was found to be active in a large number of cancers and was indicative of an altered state of the cell. These further highlight the presence of a unique gene signature as well as a target for drug therapy. The findings correlated with prognosis of myeloma patients, which was poor, as the main drug for therapy for myeloma are proteasome inhibitors.

Proteasome Inhibitor Resistance

The research team studied numerous cancer cell lines and tumors to understand the mechanism underlying proteasome inhibitor resistance. It was found that in cancers, there was suppression of the development of one or more of the subunits of the proteasome. The proteasome is made up of different sub-units that bind together to form a whole molecule. When there is a deficiency of one sub-unit, then the entire unit will not function. The failure to assemble the whole cap results in resistance to proteasome inhibitor resistance.

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Senior scientists at Whitehall Institute and senior author of the study, Luke Whitesell, state that mechanism of resistance to proteasome inhibitors highlights the complexity of the development of resistance to chemotherapy

Biomarker Identified

The findings of the study provided a new biomarker for drug targets in cancer therapy. The proteasome inhibitors resistance mechanism highlighted the presence of a gene signature which can be used for stratifying patients. Pharmacogenetics is an important factor in ascertaining the mode of treatment for many cancer patients. Certain variants of genes will respond to certain drug therapies while certain others will not. The gene signature that was identified in the current study could be used in identifying which patients have a higher risk of developing proteasome inhibitor resistance and which patients would respond to treatment.

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Dr. Tsvetkov stated that the gene signature is an indication of a heritably changed state which is of therapeutic significance in a number of cancers, a variance in a gene that addresses vulnerability to the different cancer drugs which are already commercially available. The resistance to cancer drugs can be achieved by multiple mechanisms, which include genetic as well as epigenetic factors, however, the author states that “these findings point us to new strategies and novel compounds that can be developed as treatments that will be more effective for an array of cancer types because they are less susceptible to the emergence of resistance.”

References:

1. The proteasome: structure, function, and role in the cell. - (https://www.ncbi.nlm.nih.gov/pubmed/12738238)
2. Proteasome inhibitors in cancer therapy - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088792/)

Source-Medindia