Two-pronged attack against lung cancer could overcome EGFR drug resistance

Lung X-ray
University of California, San Francisco, researchers believe combining EGFR inhibitors with Aurora kinase blockers could overcome drug resistance in lung cancer. (National Institutes of Health)

Targeting mutations in the EGFR gene has proven effective for treating some patients with lung cancer, but drug resistance remains a challenge. Many patients relapse after experiencing long-term remissions of up to two years. Now, scientists at the University of California, San Francisco, say they’ve figured out why lung cancers become resistant to EGFR-targeting therapies—and their insights could lead to new combination strategies for treating patients.

EGFR mutations cause the machinery that controls cell division to get stuck in the “on” position, leading to abnormal cell proliferation and cancer. Drugs that target the mutations, such as AstraZeneca’s Tagrisso, inhibit EGFR and control tumor growth. But over time, tumor cells rewire themselves so they can continue to grow even without the presence of the mutated protein produced by the faulty gene.

The UCSF team discovered that in acquiring resistance to EGFR inhibitors, tumor cells activate a protein called Aurora kinase A. Aurora shuts down the ability of cells to commit suicide, thus guaranteeing tumor cells will survive regardless of what the EGFR gene is doing.

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Combining EGFR inhibitors with drugs targeting Aurora kinase A killed cancer cells permanently and caused lung tumors in mice to shrink, the UCSF team discovered. They published their discovery in the journal Nature Medicine.

RELATED: Lilly regains an oncology asset in up-to-$575M AurKa deal

The UCSF researchers made their discovery by first treating multiple EGFR-mutated cancer cells with either Tagrisso or rociletinib, the latter of which was an EGFR inhibitor developed by Clovis Oncology that failed in phase 3 testing. The cells eventually stopped responding, after which the researchers tested 94 different drugs to see whether they could reverse the resistance.

That’s when they discovered that combining Tagrisso or rociletinib with drugs targeting the Aurora kinase killed off the cells permanently. They wanted to observe the effect of the combo in a living model, so they transplanted drug-resistant tumors into mice. In animals treated with EGFR inhibitors alone, the tumors continued to grow, but the two-drug combo promoted tumor shrinkage. The researchers also discovered that Aurora can’t make tumors grow on its own—it merely provides an escape hatch for cancer cells to avoid death.

“Aurora kinase was never before associated with drug resistance in cancer. It’s a fundamentally new pathway for resistance to emerge,” said senior author Sourav Bandyopadhyay, Ph.D., UCSF associate professor of bioengineering and therapeutic sciences, in a statement.

Aurora kinases are already well known in the oncology community. In May, Eli Lilly took back an Aurora kinase A inhibitor it had originally developed by acquiring AurKa Pharma in a deal that could be worth up to $575 million. Lilly is developing AurKa’s lead asset, AK-01, in solid tumors.

Other companies have struggled with Aurora kinase inhibition, however. One drug in that class, alisertib, was at the center of Takeda’s $8.8 billion acquisition of Millennium Pharmaceuticals in 2008, but seven years later the drug flopped in a late-stage lymphoma trial and the company pulled the plug on its development.

The UCSF researchers believe a combination approach will be key to reviving interest in Aurora kinase inhibition—and they’ve identified a biomarker that clinicians would be able to use to identify the patients most likely to respond. By studying tumor samples from several patients with late-stage, drug-resistant lung cancer, they discovered elevated levels of a protein called TPX2.

The team plans to work toward gaining approval to test a TPX2 diagnostic along with the two-drug combo in clinical trials.

“We hope this work re-invigorates pharma interest in cell cycle inhibitors such as Aurora kinase inhibitors,” Bandyopadhyay said. “We believe that this class of molecules has incredible power when combined with other targeted therapies, which is not how they have been tested historically.”