Editor's note: This is part two of a two-part series on receptor tyrosine kinases in cancer. Part one ran in Thursday's issue.

From an oncologist's perspective, the receptor tyrosine kinases, or RTKs, are collectively a bunch of troublemakers. But to date, the theory is that in any given cancer, the family has one black sheep.

"The prevailing view has been that most cancer cells have a single mutated RTK that really carries the day," in terms of driving uncontrolled cell growth, Ronald DePinho, American Cancer Society research professor at Harvard Medical School's Dana-Farber Cancer Institute, told BioWorld Today.

Findings published online in the Sept. 13, 2007, issue of Sciencexpress by senior author DePinho, first author Jayne Stommel and their colleagues suggested the role of receptor tyrosine kinases in cancer may be more akin to that of a crime syndicate: They found that in most glioblastomas, "there are multiple RTKs that are simultaneously activated."

The researchers, who are from the Dana-Farber and the Memorial Sloan-Kettering Cancer Center in New York, used antibody-binding studies to test for receptor tyrosine kinase activation in 20 glioblastoma cell lines. They found that in 19 of those lines, at least three RTKs were activated - a finding the team subsequently replicated in several other solid tumor types.

DePinho and his colleagues then tested the effects of treating cells with multiple activated receptor tyrosine kinases with Gleevec (imatinib, Novartis AG), Tarceva (erlotinib, Genentech Inc. and OSI Pharmaceuticals Inc.), the Met kinase inhibitor SU11274, or short interfering RNAs, alone or in combination. They found that while the drugs had either modest or no effects when each was used singly, a multidrug regimen was much more effective in stopping cell growth in its tracks. That was the case even when the downstream element PTEN also was mutated; in glioblastoma patients with PTEN mutations, single RTK inhibitors are completely ineffective.

The findings may explain why, despite the excitement surrounding them, response rates to receptor tyrosine kinases have been low and survival advantages often have been modest. While it remains to be seen whether combination therapy is as useful in patients as it is in cell lines, DePinho believes the results certainly justify testing such combinations.

The work should have "an immediate and transformative effect on the design of clinical trials," he said. "The findings support the view that trials in the RTK space should be directed against more than one RTK, and patients should have their RTK profile evaluated" to determine which kinases need to be shut off in that individual.

At first blush, it seems like that approach might be a tough sell regardless of its medical merits. After all, even as single agents, both Gleevec and Tarceva, which cost thousands of dollars per month of treatment, are among the poster children for exploding health care costs.

But DePinho argued that the increased direct costs will be more than offset by higher success rates of combination therapies. The high cost of therapeutics, he said, is "driven in large part by high development costs." And what drives those costs up is not primarily the fact that cancer medications are expensive, but that most of those expensive medications then fail. The chances of success of a cancer drug entering clinical trials to ultimately garner FDA approval are less than 10 percent. Increasing the odds of clinical trial success ultimately would mean that the price of drugs could come down accordingly.

RTKs converge on a few growth pathways, and there are critical factors such as PI3 kinase and PTEN downstream that are being targeted clinically as well. But DePinho gives the multipronged attack higher chances of success than single-agent approaches targeting downstream points.

The reason, he said, is that "while there are perhaps more rate-limiting genetic factors, these pathways are all intersecting in enormously complex, context-specific ways." And those complex interactions often can help cancer cells get around single-agent roadblocks, keeping pathways activated via alternate routes when the primary highway is blocked.