A protein which mocks anti-cancer therapies

Hypoxia explains how the mTOR protein scoffs at therapeutic anti-cancer strategies

Does hypoxia – reduced oxygen supply – explain the weakness of the response to anti-cancer treatment targeting the mTOR protein? A promising target, but one which in effect thwarts therapeutic strategies. International researchers, including Françoise Remacle at the University of Liège, have called upon the concepts of physical chemistry to study this complex biological system. And their results, published in the prestigious American journal PNAS, confirm and describe the role of hypoxia on the protein’s activity

The University of Liège, the Hebrew University of Jerusalem, the California Institute of Technology and the University of California, Los Angeles, have worked together on studying the influence of hypoxia (reduced oxygen supply) on the molecular signalling of the mTOR protein – which constitutes a promising therapeutic target – in a brain tumour model. Françoise Remacle, FNRS Research Director and Director of the Theoretical Physical Chemistry Laboratory, within the University of Liège’s Department of Chemistry, has just co-written an article entitled ‘Hypoxia induces a phase transition within a kinase signaling network in cancer cells’ in the prestigious American science journal PNAS (Proceedings of the National Academy of Sciences).

Solid cancer tumours are more often than not subjected to reduced oxygen pressure (hypoxia), which can affect the ways in which they respond to treatment. The mTOR protein (mammalian Target Of Rapamycin) plays an important role in the regulation of cell response to environmental molecular signals and is activated in a very significant manner in several solid tumours. For this reason mTOR constitutes a promising therapeutic target but the results of therapies inhibiting mTOR are not conclusive. It has moreover been established that the molecular signalisation of mTOR is affected and impaired by reduced oxygen pressure.

The goal of this collaboration between researchers at the University of Liège, the Hebrew University of Jerusalem, the California Institute of Technology and the University of California, Los Angeles, was to study the influence of hypoxia on the molecular signalisation of mTOR in a brain tumour model and to determine if the latter could be responsible for the low levels of success of therapies targeting mTOR. The use of a new microchip technology has enabled the response of the molecular signalling of mTOR to be measured for unique cells. The results where then interpreted thanks to a theory based on the concepts of physical chemistry.

This combined experiment-theory approach has enabled the researchers to bring to light essential elements of this complex system’s response. They show that at a given level of oxygen pressure reduction which is common in solid tumours, mTOR does not respond to treatment and that its molecular signalisation changes character depending on the value of this oxygen pressure. This transition has analogies with a transition phase, a type of response which has not yet been characterised in biological systems. The results explain the weak therapeutic activity of mTOR inhibitors. They also illustrate the fact that a combined theoretical and experimental approach, using concepts from physical chemistry, can be useful in explaining the response of complex biological systems and the development of new therapies.

Françoise Remacle contributed to this study from the point of view of developing the theory and analysing the results using the concepts of physical chemistry.

Reference

« Hypoxia induces a phase transition within a kinase signaling network in cancer cells » in PNAS, 25/03/201. DOI : 10.1073. http://www.pnas.org/content/early/2013/03/20/1303060110.abstract
 
Authors: Wei Weia (California Institue of Technology, Pasadena), Qihui Shia (California Institue of Technology, Pasadena), Francoise Remacle (Université de Liège), Lidong Qin (California Institue of Technology, Pasadena), David B. Shackelford (University of California, Los Angeles), Young Shik Shin (California Institue of Technology, Pasadena), Paul S. Mischel (University of California, Los Angeles), R. D. Levine (University of California, Los Angeles – Hebrew University of Jerusalem), James R. Heath (California Institue of Technology, Pasadena).