Researchers from the Catalan Institute of Oncology (ICO), the Bellvitge Biomedical Research Institute (IDIBELL), the Spanish National Cancer Research Center (CNIO) and the Dana-Farber Cancer Institute of the Harvard Medical School (USA) participated in the study too.
Alternative strategy to block the KRAS gene
Mutations of the KRAS gene occur in over 90% of pancreatic carcinomas. The gene helps the cell to interpret what is happening outside and indicates what actions must be done next, for instance to reproduce itself or to die. Oncogenic mutations of the gene occur mostly in pancreatic, colon and adenocarcinomas in the lung. So, it always signals cells to proliferate, independently of the information that comes from outside.
Scientists have unsuccessfully tried to inhibit KRAS during more than thirty years in order to stop tumour development. “The strategy applied by the research team is to know better how the cell regulates its activity and how KRAS acts; therefore, if we are not able to inhibit directly the action of oncogenic KRAS, we try to hamper its interaction with other proteins in order to avoid its action and influence on tumours”, explains Neus Agell.
Reduction of tumour growth
Researchers, together with the Proteomics Unit of the Scientific and Technological Centres of the UB (CCiTUB), studied the proteins that interact with KRAS in cancer cells. Among candidate proteins, the protein HNRNPA2B1 was selected. The next step was to knock down the protein in two different cell lines of pancreatic ductal adenocarcinoma (PDAC) —the most common type of pancreatic cancer— in order to observe the effects on tumour growth. Down-regulation took place, first, in cancer cell lines than need mutated KRAS gene in order to develop —they are named KRAS-dependent cell lines— and, second, in cell lines where the tumour can develop without KRAS. “Silenced HNRNPA2B1 protein reduced cancer cell proliferation and growth and increased cell death, but only in KRAS-dependent cell lines”, points out Neus Agell.
The effects were repeated later when these human cancer cells were injected in mice. Again, when the protein HNRNPA2B1 was silenced, KRAS-dependent cell lines showed a significant reduction of tumour growth.
In the search for potential therapeutic targets
Results obtained from this study can be added to the ones got in a previous work in which the research team found other molecules which are also involved in regulating KRAS activity in the cell. To be exact, researchers found an enzyme that plays a key role in a process named phosphorylation, in which a phosphate is added to KRAS gene. “We proved in mouse cells that if the enzyme is inhibited, KRAS signalling is reduced and cell’s oncogenicity decreases too. Consequently, we can approach KRAS in two different ways: by depleting its interaction with the protein HNRNPA2B1 or by preventing phosphorylation”, affirms Montserrat Jaumot, UB and IDIBAPS researcher who also signs the scientific paper.
The next step to be made by the IDIBAPS and UB research team is to know better how KRAS alterations work in order to design drugs able to block them. “In order to break these interactions, it is necessary to know in detail what happens at biochemical and molecular levels when KRAS oncogenic functions take place”, concludes Neus Agell.
Source: UB
Article Reference:
Carles Barceló, Julia Etchin, Marc R. Mansour, Takaomi Sanda, Mireia M. Ginesta, Victor J. Sanchez-Arévalo Lobo, Francisco X. Real, Gabriel Capellà, Josep M. Estanyol, Montserrat Jaumot, A. Thomas Look, Neus Agellemail
Received: July 30, 2013; Accepted: June 29, 2014; Published Online: July 03, 2014
DOI: http://dx.doi.org/10.1053/j.gastro.2014.06.041