Some Anticancer Drugs Stop Working at a Hypoxia-Induced Phase Transition Point

By applying physical science analytical techniques and a basic understanding of the principles of thermodynamics to the problem of drug resistance in cancer cells with mTOR (mammalian target of rapamycin) mutations, cancer researchers identified a hypoxia-induced phase transition point at which mTOR suppressing drugs were no longer effective.

Hypoxia is a near-universal feature of solid tumors, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. Similarly, it has been known that the behavior of mTOR signaling was influenced and altered by hypoxia, but the mechanism behind this was unknown.

Investigators at the Hebrew University of Jerusalem (Israel) and their colleagues at the California Institute of Technology (Pasadena, USA) and the University of California, Los Angeles (USA) worked with a glioblastoma multiforme (GBM) cancer cell model to examine the response of signaling networks to targeted pathway inhibition between 21% and 1% pO2 (oxygen partial pressure). For this study, they employed a microchip technology that facilitated quantification of a panel of functional proteins from statistical numbers of single cells. Results were interpreted using a set of theoretical tools derived from the physical sciences, which enabled the simplification of an otherwise complex biological system.

Results published in the April 9, 2013, issue of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) revealed that near 1.5% pO2, the mTOR signaling network - a critical component of hypoxic signaling and a compelling cancer drug target - was deregulated in a manner such that it became unresponsive to mTOR kinase inhibitors. While being unresponsive to mTOR kinase inhibitors near 1.5% pO2, cancer cells did respond at higher or lower pO2 values. These findings were validated through experiments on bulk GBM cell line cultures and on neurosphere cultures of a human-origin GBM xenograft tumor.

The investigators concluded that, "Our analysis—which may help explain the undistinguished performance of mTOR inhibitors in certain clinical trials—indicates that certain biologically complex cell behaviors may be understood using fundamental, thermodynamics-motivated principles."

Related Links:
Hebrew University of Jerusalem
California Institute of Technology
University of California, Los Angeles