Reusing Approved Kinase Inhibitors May Minimize Drug Resistance

Several anticancer agents already approved by the US Food and Drug Administration (FDA) may have unexpected activity against various mutant kinases, including ALK, LRRK2, RET, and EGFR.  A new study is suggesting some agents may be repurposed to help treat other tumor types.

This study was just published in the January 2016 issue of Cell Reports.

Patients often develop resistance to kinase inhibitor therapies and experience side effects because the inhibitors nonselectively affect a broad range of kinases. Now, researchers are reporting that they have used an innovative approach to simultaneously tackle both of these problems. In addition, they say the new finding may pave the way for new strategies to improve the effectiveness and safety of kinase inhibitors for the treatment of various types of cancer.

“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 Cancer Center, in a news release. “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.”

Dr. Peterson and colleagues 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. The 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. The researchers also identified several approved drugs that unexpectedly inhibit kinases with resistance mutations.

To date, the FDA has approved more than two dozen kinase inhibitors, many of which gained approval in just the past 3 years. However, the targeted kinases often have unintentional effects on untargeted kinases, which cause side effects such as anemia, nausea, vomiting, and diarrhea. In addition, the targeted kinases often acquire mutations that confer resistance against the drugs.

The results from the study revealed lead compounds with unexpectedly selective activity against various mutant kinases.

The analysis showed that an inhibitor of the highly resistant mutated form of a kinase known as EGFR is more selective than afatinib (Gilotrif), which is clinically approved for the treatment of non-small cell lung cancer. The researchers also identified several approved drugs, including sorafenib (Nexavar) and pazopanib (Votrient), that inhibit a mutated form of a kinase called PDGFRα, which is associated with resistance to an approved kinase inhibitor called imatinib (Gleevec) in patients with chronic eosinophilic leukemia.

“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,” said Peterson.

Researchers are looking to test some of these repurposed targeted therapies in other clinical trials, but also taking into account the potency of the drugs against new targets.