An Italian-led international research team, coordinated by Stefano Santaguida of the European Institute of Oncology (Ieo) and of the State University of Milan, has discovered a hitherto unknown cause of the ‘invulnerability’ of some forms of cancer to therapies. In technical jargon it is called chemoresistance and is the mechanism by which the cancer cell builds a barrier capable of blocking the action of drugs, neutralizing it. The study – supported by the Airc Foundation and published in ‘Developmental Cell’ – explains that “at the origin of the phenomenon there may be a known chromosomal anomaly called aneuploidy, or a variation in the number of chromosomes”, present in about 90% of solid tumors. and in 75% of those blood.
“Our work makes an important contribution to understanding the causes of chemoresistance, a risk that also looms over the most effective anticancer drugs – says Santaguida, Group Leader of the Ieo’s Genomic Integrity Laboratory and professor of molecular biology at the University of Milan – We have shown that cancer cell is capable of exploiting its own ‘internal chaos’, thus surviving even in conditions of important stress, such as the fatal attack of a chemotherapy drug. Everything seems to start “precisely” from aneuploidy, a change in the number of chromosomes “which characterizes the diseased cell and results in genetic instability. “This instability underlies the cellular chaos characteristic of cancer, which disrupts the normal functioning of the cell. It is as if the cells are constantly ‘shuffling the cards’”, Santaguida exemplifies.
“This continuous remixing – explains the scientist – can be exploited by a cancer cell, which thus survives. By continually upsetting its genetic makeup, when it is attacked by a molecule of chemotherapy,” the sick cell “can better select its’ poker d ‘axes’, that is the chromosomal patrimony (karyotype) capable of resisting the drug. This may explain why in some patients chemotherapy sometimes does not achieve the desired results “.
Aneuploidy – explains a note from Ieo and UniMi – has long been the subject of study by the Santaguida group, first as a target to target the tumor and now also as a tool to combat drug resistance. To test the effects of chromosomal instability on cell proliferation in the presence of a chemotherapy agent, the researchers exposed cultured tumor cells to a battery of chemotherapy drugs, comparing the results before and after exposure.
“We used different types of tumor cells in culture, obtained from different types of cancer including colon, lung and pancreas – reports Marica Ippolito, first author of the study and PhD student in molecular medicine at the Ieo – The cells were continuously exposed to anticancer agents routinely used in the clinic. Among the conditions tested, we found combinations that offered an advantage to these cells, in terms of survival, in about one in 5 cases. “
“The clinical implication of our discovery is very relevant – comments Santaguida – Our goal is to include the analysis of the karyotype in the study of the tumor profile, which we already carry out today and which allows us to obtain a more precise treatment. The patient-by-patient study. karyotype of cancer cells, if confirmed in preclinical and clinical studies, could be an extra step towards a more effective and precise medicine. If we identify which karyotype causes chemoresistance, we can immediately understand which combination of drugs to use to avoid this phenomenon and provide treatments more capable of eradicating cancer cells. The data from world cancer research – concludes the scientist – confirm that to find the cure for cancer, the ‘magic pill’, we need to know the inside of the cancer cell, that is to say what happens internally at the molecular level. Our study goes exactly in this direction. “