Later-stage cancers thrive by finding detours around drug roadblocks

Later-stage cancers thrive by finding detours around roadblocks that cancer drugs put in their path, but a Purdue University biochemist is creating maps that will help drugmakers close more routes and develop better drugs.

Kinase enzymes deliver phosphates to cell proteins in a process called phosphorylation, switching a cellular function on or off. Irregularities in phosphorylation can lead to uncontrolled cell growth and are a hallmark of cancer.

Many successful cancer drugs are kinase inhibitors, which block the ability of a kinase to bind with a particular protein on the cell, stopping phosphorylation and the creation of cancer cells.

W. Andy Tao, a Purdue associate professor of biochemistry and member of the Purdue University Center for Cancer Research, said that in later stages of cancers, kinase-inhibiting drugs are ineffective because the kinases adapt, finding new protein targets and forming new cancer cells. He believes that creating maps of all the potential routes for cancer cell formation is a key to developing better cancer drugs.

"I would say that 99 percent of these drugs are effective for a few months in late-state cancers, and then the cancers develop resistance," said Tao, whose findings were published online early in the Proceedings of the National Academy of Sciences. "In the beginning, the cell cannot adjust and it dies. In later stages, the cells find a way. Cancer cells find a way to survive. You block one pathway, and they find another."

The kinase-protein maps Tao is creating identify kinases and the direct protein targets they phosphorylate. His method weeds out other proteins that are not direct targets, but are later phosphorylated as part of a cascade of reactions that begins when direct target proteins are phosphorylated.

Tao compared cells with and without kinases. The phosphoproteins present only when a kinase was present were considered possible targets. Further, the proteins were dephosphorylated, meaning the phosphate groups that had been added by kinases were removed.

The kinase was then re-introduced, and those proteins that accepted phosphate groups from the kinase were deemed direct targets of that kinase. With that information, drugmakers could tailor kinase-inhibiting drugs to ensure that the drug would stop kinases from reaching all potential targets, making the drugs more effective.

"If you understand the network, you can block all the pathways to cure the cancer," Tao said.

Tao's research findings focused on the SYK kinase, which is involved in leukemia and breast cancers. He plans to study other kinases, as well as mutated kinases, to understand whether they have different protein targets.