Drug combo may help treat previously resistant tumours

London, Dec 1 : A team of scientists has discovered a potential treatment for a group of tumours that have resisted previous targeted therapy approaches.

While conducting a study, researchers from Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH) Cancer Center, and Beth Israel Deaconess Medical Center (BIDMC) Cancer Center found that combining two different kinase inhibitors - drugs that interfere with specific cell-growth pathways - led to significant tumour shrinkage in mice with lung cancer driven by mutations in the K-Ras gene.

In addition to their association with nearly 30 percent of cases of non-small-cell lung cancer, K-Ras mutations are involved in many cases of colon cancer and most pancreatic cancers, which are extremely resistant to treatment.

"Finding a way to effectively treat K-Ras-mutated cancers would be a huge advance in solid tumour oncology, since these mutations are common in several incurable cancers," Nature quoted Jeffrey Engelman, MD, PhD, of the MGH Cancer Center, one of the report's co-lead authors, as saying.

"Cancers with K-Ras mutations have been resistant to all targeted therapies to date, and it is exciting to learn that a combination of PI3K and MEK inhibitors, two families of drugs currently in clinical development, may be highly effective in these cancers," Engelman added.

The current study began with a focus on the PI3K signaling pathway, which is key to cell survival and known to control cellular motility and adhesion. PI3K mutations have caused tumour development in laboratory studies, but their role had not yet been studied in an animal model.

For the study, the researchers developed a transgenic mouse in which administration of the drug doxycycline induces the expression of cancer-associated PI3K mutations, leading to development of lung tumours. Treatment of those animals with an investigational PI3K inhibitor did lead to rapid tumour regression.

Since previous studies suggested that PI3K inhibition might also block K-Ras-induced tumour development, the researchers also tested the PI3K inhibitor in mice with K-Ras-stimulated tumours.

That treatment was ineffective, but since K-Ras also activates the MEK/ERK signalling pathway, the researchers treated the animals with an investigational MEK inhibitor and with a combination of both drugs.

Treatment with the MEK inhibitor alone caused only a modest reduction in tumour size, but combined treatment with both agents caused the K-Ras-stimulated lung tumours to virtually disappear.

"For several years we have known that K-Ras activates two major pathways - the PI3K pathway and the MEK/MAPK pathway - and that these pathways have many redundant functions in tumour growth and survival," says Lewis Cantley, PhD, of the BIDMC Cancer Center, one of the study's co-corresponding authors. Inhibitors of both of these pathways are now in clinical trials, and in this paper we show that, while either agent alone has a minor effect on K-Ras-driven tumours in mice, combining inhibitors of both pathways eradicates these tumours with minimal toxicity," Cantley added.

The study appears online in Nature Medicine.

ANI