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Scientists discover why some cancers are multi-chemoresistant

The IDIBELL group led by Manel Esteller has identified a molecular mechanism that mainly affects colorectal and stomach cancers

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10.11.2016

Researchers from the IDIBELL Cancer Epigenetics and Biology Program (PEBC) led by Manel Esteller have identified a molecular mechanism that explains why some cancers don't respond to conventional treatment with chemotherapy. The study, published in the journal Proceedings of the National Academy of Sciences (PNAS), shows that this phenomenon happens mainly in colorectal and stomach cancers and could help better classify patients and personalize treatment.

Chemotherapy has proven effective in a wide range of patients; however some of its main problems lie in resistance developed to the anti-tumor drug used. Nevertheless, for decades now we have known that there are tumors with cross resistance to various drugs from the very beginning, even before treatment.

10% of colon and stomach tumors show multi-chemoresistance due to the inactivation of a non-coding RNA fragment: the TP53TG1 molecule. In healthy tissue, the p53 protein –a tumor-suppressing protein– bonds with the TP53TG1 molecule and activates it. Once activated, this molecule blocks activation of the YBX1 protein that, when activated, goes into the cell nucleus and activates hundreds of oncogenes.

Silencing the IncRNA TP53TG1 molecule in cancer cells causes the p53 protein to lose most of its protective effect against tumors and gives the YBX1 protein free reign to activate oncogenes that prevent the death of malignant cells in spite of anti-tumor drugs, leading to resistance to chemotherapy drugs.

According to the study, this molecular process is behind resistance to the most common drugs used to treat cancer, including 5-fluorouracil, oxaliplatin and irinotecan, as well as new drugs with very recent molecular targets, such as kinase inhibitors.

Esteller’s group is now proposing to study whether some drugs are immune to this multi-resistance mechanism, and has also opened the door to the possibility of developing other drugs that restore normal activity of the TP53TG1 molecule. DNA methylation is what leads to the silencing of this IncRNA molecule, so it is an epigenetic factor (nonhereditary) that could be treated more easily. However, for now it isn't clear which environmental factor causes this epigenetic mutation in tumor cells.

 

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Resistència quimioteràpia

Cross-section of stomach cancer under a microscope, showing aberrant expression of YBX1 protein (tinted brown) - Photo: © IDIBELL.