Using a novel systematic method, scientists found that breast cancer cells use Aurora kinase A to evade being targeted by drugs inhibiting the PI3K pathway. Blocking this protein restores the therapeutic potential of previous ineffective cancer therapies.
The study with that finding, “Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer,” was published recently in Nature Chemical Biology.
More than 60 percent of breast cancer cases involve defects in the PI3 kinase (PI3K) pathway, which is a biochemical cascade that spurs the growth and survival of cancer cells when abnormally activated.
While this has made PI3K a promising pharmaceutical target for several types of tumors, the clinical effectiveness of PI3K inhibitors for cancer treatment achieved little success in previous trials, leaving researchers with no clue to account for its failure.
“The failure of PI3 kinase drugs has been a huge mystery,” Sourav Bandyopadhyay, PhD, said in a press release. Bandyopadhyay is assistant professor of bioengineering and therapeutic sciences and a faculty member of the UCSF Helen Diller Family Comprehensive Cancer Center, .
Even Novartis’s Afinitor (everolimus) — an inhibitor of the mTOR kinase that also is involved in the PI3K pathway and was approved by the U.S. Food and Drug Administration for the treatment of advanced recurrent breast cancer — usually prolongs patient survival for only a few months.
“Every pharma company in the cancer space has tried to target the PI3 kinase pathway, with little success. Now we may know why,” Bandyopadhyay said.
Because so many drugs targeting kinases from the PI3K pathway failed, Bandyopadhyay’s team decided to take a closer look at other types of kinases that are not directly involved in cancer growth, but might still play a role in tumors’ drug resistance. “Instead of looking at one drug, one tumor or one kinase, we took a systematic view,” he said.
Using an unbiased screening approach called mass spectrometry to identify and quantify kinases purified with microscopic beads from human breast cancer cells grown in lab dishes and in mice, investigators mapped the activity of 151 kinases in response to several PI3K inhibitors.
With this method, researchers found that Aurora kinase A — a protein previously thought to be harmless — seemed to be the missing link that was conferring drug resistance to breast cancer cells.
“The presence of Aurora kinase A causes resistance to every drug targeting the PI3K-pathway that we tested,” Bandyopadhyay said. “We found other hits, but it was the top-ranked by far.”
Then, in order to see if blocking Aurora kinase A would restore the therapeutic effectiveness of PI3K inhibitors, researchers tested alisertib (MLN8237), an experimental drug that specifically inhibits Aurora without affecting the PI3K pathway. Remarkably, the combination of MLN8237 with Afinitor stopped the growth of the tumor and activated a cellular suicide program that killed malignant cancer cells.
Investigators then tested the combination treatment in 12 types of human breast cancer cells grown in the lab and in animal models, and observed the same fatal effect for most of them.
All the mice that received the combination treatment had their tumors shrunk, while those receiving Afinitor alone only had a minor reduction of tumor growth. Importantly, the combination of MLN8237 with Afinitor was not toxic at the dosages used in this study.
“There have been more than 200 clinical trials with experimental drugs that target the PI3K pathway, and probably more than $1 billion invested, with only one approved drug treatment so far,” Bandyopadhyay said. “We believe the reason these drugs have not been more successful in the clinic is because of proteins that, when they are present in tumor cells, cause innate resistance to these drugs. We now have methods and technology we can use to identify these proteins,” he said.
“This work has immediate clinical implications, and we hope this study spurs interest in combining these two classes of embattled cancer drugs. These data clearly warrant clinical testing and we are working to put together a Phase 1 clinical trial to test such drug combinations in patients,” Bandyopadhyay concluded.