Mechanism determined for treating the most aggressive tumours
A study led by researchers from the Hospital del Mar Medical Research Institute (IMIM), has determined, for the first time, the importance of a cell mechanism that may be key to treating metastatic tumours. The work has demonstrated the role a protein, kinase IKKα, plays in the ability of tumour cells to repair themselves. This is a key factor in treatment resistance and tumour spread. The research has been published in the journal Molecular Cell.
The researchers analysed the role of this protein, activated by mutations of the BRAF and KRAS oncogenes, present in the majority of the most aggressive tumours. The function of this protein is to facilitate DNA-repair in tumour cells after they have been damaged by chemotherapy, making them more resistant to the action of these drugs. This is key for the treatment approach, since this new study demonstrates, conclusively, that combining a BRAF oncogene inhibitor with chemotherapy deactivates and kills the tumour.
These same oncogenes, in addition to converting normal cells into tumours, make them better able to repair the damage caused by chemotherapy agents or radiation, and make them more resistant. In other words, they play a double role, facilitating tumour transformation and protecting the tumour from the damage caused by chemotherapy and radiation. "The presence of these mutations makes treatment very difficult but this is also an advantage, because if, thanks to these mutations, the tumour cell is more resistant to damage, eliminating their activity with drugs that are currently used in clinical practice will make the tumour even more sensitive to the treatments. And that’s what we’ve demonstrated” explain the researchers.
This is a key factor in treatment resistance and tumour spread
Analysis with tumours from human patients
The researchers verified the role of the protein IKKα and its importance as a therapeutic target, implanting colon tumours, from human patients who had developed metastasis and treatment resistance, into mice. The study results showed that animals which received no treatment, or were treated only with either BRAF inhibitors or chemotherapy, died. But those that received a treatment combining these inhibitors with chemotherapy survived. What is more, the tumour cells were found to have died. This was confirmed with in vitro samples.
The researchers behind the study now want to start a clinical trial in cancer patients, taking advantage of the fact that the drugs employed in the study already exist and are used in clinical practice. Firstly, their usefulness for treating colon and rectal cancer will be analysed, but the researchers have not ruled out the possibility that they may be effective for any kind of tumour involving BRAF and KRAS oncogenes, such as pancreatic cancer and melanoma.
Carlota Colomer, Pol Margalef, Alberto Villanueva, Anna Vert, Irene Pecharroman, Laura Solé, Mónica González-Farré, Josune Alonso, Clara Montagut, Maria Martínez-Iniesta, Joan Bertran, Eva Borràs, Mar Iglesias, Eduard Sabidó, Anna Bigas, Simon J. Boulton & Lluís Espinosa. IKKα kinase regulates the DNA damage response and drives chemo-resistance in Cancer. Mol Cell 2019; 75(4): 669-682.