Ferreting out why some cancer drugs struggle to shrink tumors

In several types of cancer, including most cases of breast cancer, a cell-signaling network called the PI3K pathway is overactive. Drug designers have tried to quiet this pathway to kill cancer, but they haven’t had much success and, more frustratingly, haven’t understood why the problem is so hard to solve.

“There have been more than 200 clinical trials with experimental drugs that target the PI3K pathway, and probably more than $1 billion invested,” says Sourav Bandyopadhyay of the University of California, San Francisco. Just a handful of drugs have been approved by the U.S. FDA and one, Novartis’s Afinitor (everolimus), deters cancer growth but doesn’t shrink tumors, and it prolongs patient survival only a few months.

Bandyopadhyay, his UCSF colleague John D. Gordan, and coworkers used a proteomics approach to ferret out why previous attempts to target the PI3K pathway have had limited success and, using that information, devised and tested a possible fix (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0081-9).

The stubborn pathway involves a series of kinases—enzymes that modify other proteins by adding phosphate groups—starting with one called PI3K. Overactivation of the pathway produces the transcription factor MYC, which turns on protein synthesis and can spark cancer growth.

The UCSF team used kinase-affinity beads and tandem mass spectrometry to survey all kinases active in breast cancer cells before and after treatment with a variety of cancer drugs. The team studied this so-called kinome to look for kinases associated with the cells’ tendency to resist drug treatments.

The researchers found that a kinase called AURKA undermines everolimus and other pathway-targeted drugs by reversing their effects. While the drugs try to turn off the PI3K pathway, AURKA, activated separately by other pathways, keeps the PI3K pathway turned on. To add insult to injury, MYC boosts AURKA production, maintaining a plentiful supply of the drug spoiler.

When the researchers coadministered everolimus with the AURKA inhibitor MLN8237, also called alisertib, everolimus could inhibit the PI3K pathway as it was designed to do, without interference. The combination treatment killed most types of cancer cells in culture and shrank tumors in mice with breast cancer, whereas everolimus alone permitted slow tumor growth to continue.

Bandyopadhyay’s team is putting together a Phase I clinical trial to test such drug combinations in patients with advanced, recurrent breast cancer.

The findings raise hope that “there might be some pathway forward for PI3K targeting,” says Filip Janku, who studies the PI3K pathway at the University of Texas MD Anderson Cancer Center. “The concept deserves additional work to see if it can eventually move the needle.”

“The study is a great example of how characterizing kinome proteomics can lead to discoveries that are frequently not apparent” with other techniques, says signaling networks expert Gary L. Johnson of the University of North Carolina School of Medicine.

In a commentary accompanying the new study, cancer chemical biologist Uwe Rix and colleagues at H. Lee Moffitt Cancer Center & Research Institute write that similar proteomics studies with other cancer-related pathways and the drugs that target them “may lay the foundation for novel and greatly needed combination therapy approaches.”