Scientists identify new therapeutic targets for ovarian cancer subtypes with poor prognosis

Dr. Chan Lugan.Credit: Wistar Institute

Mutations in the ARID1A gene are present in more than 50% of clear-cell ovarian cancers (OCCCs) that lack effective treatment. Wistar Institute scientists have found that loss of ARID1A function enhances the cellular stress response pathway that promotes survival of cancer cells that are sensitive to pharmacological inhibition of this pathway. The results of these findings were published online. Cancer research, A journal of the American Association for Cancer Research, points out new treatment opportunities for this type of ovarian cancer in urgent need for new solutions.

Inactivating mutation of ARID1A Tumor suppressor gene Is a genetic driver of OCCC, does not respond to chemotherapy and has the worst prognosis of all subtypes of ovarian cancer.

“The goal of our study is to reveal the molecular changes caused by the loss of ARID1A and to specifically target them to achieve effective treatments for this catastrophic disease. That’s what we do, “said Dr. Rugang Zhang, Deputy Director of the Wistar Institute Cancer Center. , Professor and leader of immunology, microenvironment and metastasis programs, and lead author of research. “In this study, stress The response mechanism by which the tumor has found a link that it relies on for survival and provides treatment opportunities. “

The endoplasmic reticulum (ER) is the cell structure that is monitored. Protein production It has a complex mechanism for responding to stress caused by the accumulation of misfolded proteins. The endoplasmic reticulum stress response is frequently overactivated in cancer cells to promote survival in stressful microenvironmental conditions. Therefore, inhibition of this mechanism has been investigated as a therapeutic approach for cancer with overactive endoplasmic reticulum stress response.

The IRE1a / XBP1 pathway is the major signaling pathway involved in the endoplasmic reticulum stress response. The protein inositol-required enzyme alpha (IRE1a) senses endoplasmic reticulum stress and activates the transcription factor X-box binding protein 1 (XBP1) to resolve endoplasmic reticulum stress and upregulate genes that promote cell survival. Bring.

Zhang et al. Found that ARID1A inhibited the IRE1a / XBP1 pathway, and as a result, loss of ARID1A in ovarian cancer increased pathway activation and cancer cells depended on the upregulated IRE1a-XBP1. .. In fact, treatment of ovarian cancer cells that do not express ARID1A with the selective IRE1 inhibitor B-I09 caused cell death as a result of unresolved endoplasmic reticulum stress.

“In some cases, the mechanisms that cancer cells take advantage of become vulnerable because they become dependent on specific pathways,” Zhang added. “If we can find a way to block these pathways, we may be able to use them as a weakness in killing cancer.”

Importantly, this observation was confirmed in vivo because B-I09 treatment reduced tumor mass and improved survival in mouse models with ARID1A inactivated ovarian tumors.

Treatment resistance enables cancer Cells to escape the effects of monotherapy, and combination strategies, provide a solution to this key challenge. Therefore, the researchers tested a combination of IRE1a inhibition and histone deacetylase 6 (HDAC6) inhibition. It is also effective against ARID1A mutant cancers. Because HDAC6 regulates the breakdown of misfolded proteins, the team hypothesized that the two treatments could work synergistically to suppress ARID1A mutant cancer.

“Our findings suggest that pharmacological inhibition of the IRE1a / XBP1 pathway of ER stress response represents a potential therapeutic strategy for ARID1A mutant cancer, either alone or in combination with HDAC6 inhibition.” Zhang Lab and the lead author of the treatise.

The link between ovarian cancer drivers and metabolism opens up new therapeutic strategies

For more information:
Joseph A. Zundell et al, Targeting the IRE1α / XBP1 endoplasmic reticulum stress response pathway in ARID1A-Mutant Ovarian Cancers, Cancer research (2021). DOI: 10.1158 / 0008-5472.CAN-21-1545

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Wistar Institute

Quote: Scientists have obtained a poor prognosis ovarian cancer subtype (2021) from https: // on September 21, 2021. Identify new therapeutic targets (September 21, 2014)

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Scientists identify new therapeutic targets for ovarian cancer subtypes with poor prognosis

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