PHILADELPHIA (January 14, 2016) – Kinase inhibitors are a well-established component of the arsenal of anticancer drugs. But patients often develop resistance to these therapies and experience side effects because the inhibitors non-selectively affect a broad range of kinases. Fox Chase Cancer Center – Temple Health researchers recently used an innovative approach to simultaneously tackle both of these problems, paving the way for new strategies to improve the effectiveness and safety of kinase inhibitors for the treatment of various types of cancer.
In a study published January 14th in Cell Reports, lead author Krisna Duong-Ly, PhD, postdoctoral fellow at Fox Chase, examined the effects of 183 small-molecule compounds on the activity of 76 kinases, some of which carried mutations that conferred resistance to approved drugs. This unprecedentedly large-scale screen revealed lead compounds that are more selective than approved drugs against mutant kinases and therefore less likely to produce resistance or side effects in patients. The researchers also identified several approved drugs that unexpectedly inhibit kinases with resistance mutations, suggesting that these drugs could be repurposed for new indications in treatment-resistant patients.
“Patients treated with existing drugs that inhibit kinases often become resistant to those drugs because the kinases mutate so that the drugs no longer bind them. These mutated kinases can be like entirely new beasts, resistant to the drugs and relentlessly driving the growth of cancer,” said senior study author Jeffrey R. Peterson, PhD, associate professor in the Cancer Biology Program at Fox Chase. “Our studies suggest that these existing drugs, or molecules like them, could be rapidly shifted to benefit certain cancer patients that no longer respond to the current drug.”
Kinases are proteins that play a key role in a variety of cellular processes, including growth, proliferation, metabolism and death. Because these processes often go awry in cancer cells, the development of kinase inhibitors has been a major focus of cancer research. To date, the Food and Drug Administration (FDA) has approved more than two dozen kinase inhibitors, many of which gained approval in just the past three years.
However, these drugs typically bind to a specific site that is highly conserved across kinases, leading to broad, unintentional effects on untargeted kinases. For patients, this could translate into side effects such as anemia, nausea, vomiting and diarrhea. Moreover, the targeted kinases often acquire mutations that confer resistance against the drugs, so that over time patients no longer respond to treatment.
To overcome these problems, Peterson and his team conducted an unbiased screen of 183 small-molecule compounds against 76 mutant kinases. The results revealed lead compounds with unexpectedly selective activity against various mutant kinases as well as opportunities for repurposing FDA-approved kinase inhibitors.
“This study is novel primarily because of the scale of the work we’ve done. Usually, individual kinases are studied one at a time,” Peterson said. “In some cases it was surprising that some of these new drugs were right under our noses all along but because they were developed for one kinase, no one considered testing them on other, unrelated kinases.”
The analysis revealed that an inhibitor of the highly resistant mutated form of a kinase called EGFR is more selective than afatinib, which is clinically approved for the treatment of non-small-cell lung carcinoma. The researchers also identified several approved drugs—including sorafenib and pazopanib—that inhibit a mutated form of a kinase called PDGFRα, which is associated with resistance to an approved kinase inhibitor called imatinib in patients with chronic eosinophilic leukemia. “The findings suggest that it is possible to take advantage of the general, off-target effects of approved kinase inhibitors to repurpose them for new indications in treatment-resistant patients,” Peterson said.
The next step is to test some of these repurposed drugs in clinical trials. In some cases, additional work will be required to optimize the potency of these drugs against the new targets. “We hope to continue this line of research, testing more and more drugs as they are developed for activity against more and more kinases that drive cancer and other diseases,” Peterson said. “There are probably many more exciting discoveries like this just waiting to be found.”