Science Editor

Cancer's multiple ways to get around nontargeted and targeted treatments alike provide multiple headaches to drug developers.

From a market perspective, developing a dozen agents for a dozen forms of resistance is bad enough when those dozen forms of resistance are occurring in a dozen patients.

But in advanced tumors, those dozen mutations can occur in the same patient.

"In late-stage patients, their tumors are very heterogeneous," Dihua Yu told BioWorld Today, "and it makes them very challenging to treat – you cannot give them 10 drugs," as chances are the side effects would kill them more quickly than the tumor itself.

The trick, then, is to identify critical spots in cellular signaling pathways where resistance pathways converge. In the March 13, 2011, online edition of Nature Medicine, senior author Yu, who is professor of molecular and cellular oncology at the University of Texas M.D. Anderson Cancer Center, and her colleagues reported they have identified such a downstream point of convergence for Herceptin-resistant tumor cells: the SRC kinase.

Even in patients overexpressing the her2 receptor, Herceptin can be a miracle drug or a dud, depending on the rest of that tumor's genetics. Only about a quarter of patients respond to Herceptin as a single agent, and in combination with other treatments, about 40 percent of patients fail to respond.

There had been "many papers reporting different mechanisms" for that resistance, Yu said. Her team identified SRC kinase as a "key node" whose targeting "can reverse resistance from all these different mechanisms."

The authors identified SRC as one kinase that is activated by "breeding" resistant cell lines through long-term Herceptin exposure. They found that SRC can be activated by a variety of other kinases that have been linked to Herceptin resistance. In tumor samples, SRC activity was linked to Herceptin resistance as well as reduced life expectancy.

The team next tested whether Herceptin's performance could be improved by combining it with the SRC inhibitor saracatinib. Saracatinib has been previously tested in the clinic by AstraZeneca plc as a single-agent treatment. In those trials, it had somewhat homeopathic-like qualities: "It had no side effects," Yu said. But it had no efficacy either.

Saracatinib shone, though, when Yu and her team tested it in combination with Herceptin. The authors tested the combination in four cell lines, each with a different mutation that rendered the cells resistant to Herceptin. In all four cases, the combination of the two drugs killed the cells.

The combination was also successful in animal studies. In one tumor model, the authors wrote, "combinatorial treatment eliminated tumors and most tumors were barely detectable 21 days after treatment," while either agent alone had little or no effect.

The work advances the scientific understanding of cancer signaling pathways, as well as pointing to a possible clinical strategy. SRC is a target of PTEN, a much-studied tumor suppressor gene. PTEN is a phosphatase, which opposes kinases by removing phosphate groups; by removing phosphate groups from SRC, it deactivates the protein, keeping it in check.

"We identified a protein substrate for PTEN," Yu said. PTEN affects both lipids and proteins, and its lipid targets are well known; but its protein target had not been, and "it was not clear before . . . how important its activity on its protein substrate is in tumor biology."

Yu is hoping to test the combination of Herceptin with SRC inhibition in the clinic, though AstraZeneca is not currently developing the drug, given its previous clinical failure. Yu hopes that she will be able to at least secure enough drug from the company for a clinical trial; another possibility is to use dasatinib, which also inhibits the SRC kinase, though its side effects are more pronounced than those of saracatinib.

Given the cat-and-mouse game that targeting resistance is, Yu acknowledged the possibility that cancer cells will develop resistance to SRC kinase inhibitors as well, once the pressure is on. But when such resistance does develop, she said, "we can identify and target those mechanisms." And in the meantime, "we have patients that are dying. . . . We want to save their lives."