Saturday, April 10, 2010

Drug resistance

This paper has just appeared in Cell.

A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations
Sreenath V. Sharma et al Cell 2010 DOI 10.1016/j.cell.2010.02.027

Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly ‘‘drug-tolerant’’ cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells
transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.

In other words some cancer cells can only become resistant to anti-cancer agents by using a little-used pathway to keep alive. Block that pathway and they die. Some evidence that drug resistance in cancer cells may be reversible.


Anonymous said...

I'm not holding my breath. Whatever happened to that nutlin thing you were talking about a while back? And that, what was it, the PARP inhibitor or some such?

Both DOA?

If I had a dollar for every news story or press release that said 'researchers are excited about...' I'd have some real money.

I learned to ignore sound in the bushes unless something not only get into clinical trials, but makes it to stage III.

I'm sorry but little (if anything) pans out in the end.

Terry Hamblin said...

A trial of thr PARP1 inhibitor has just started in Birmingham, UK. It is already in action against BRCA1 positive breast cancer. Nutlin is bing trialed in liposarcoma first. I'm afraid these trials are long winded affairs. Moves are afoot to shorten how long they take, but as usual it is money that holds things up.