Lung cancer patients with EGFR mutations often respond to targeted treatments but then become resistant in a few short months. Now, researchers led by a team at the University of Toronto believe they’ve found a way to correct this drug resistance with two recently approved medicines for leukemia.
Using a cell-based technology developed at the university’s Donnelly Centre for Cellular and Biomolecular Research, the researchers hit upon Astellas’ Xospata (gilteritinib) and Novartis’ Rydapt (midostaurin) as potential treatments for non-small cell lung cancer (NSCLC) with triple-mutant EGFR. They are now planning human trials, starting with Astellas’ product, they reported in the journal Nature Chemical Biology.
About 20% of NSCLC patients in North America have EGFR mutations, which can be targeted with kinase inhibitors. Eventually, though, the tumors take on new mutations that make them resistant to these drugs. AstraZeneca’s Tagrisso was approved by the FDA in 2017 to treat patients who develop resistance mutations, and it has chalked up impressive survival statistics since then. Still, many patients develop yet another mutation, called C797S, which causes their tumors to escape Tagrisso treatment.
The University of Toronto researchers developed a tool to identify drugs that can enter cells and target specific receptors. The live-cell model allows them to observe how drugs target kinase activity and interact with other proteins in the cell. They used the model to screen nearly 3,000 molecules in search of those that could target the C797S mutation in triple-mutant EGFR.
Xospata and Rydapt emerged as drugs that can hit the mutation without harming healthy cells. The University of Toronto team also turned up another promising candidate, called EMI1, which acts in a novel way. Instead of inhibiting kinase activity, EMI1 recruits other molecules to degrade the receptor—a mechanism of action that they believe will inhibit the formation of resistance mutations.
The team is now working with the Ontario Institute for Cancer Research to fine-tune EMI1 in the hopes of testing it in animal models of resistant cancer.
Finding new ways to overcome resistance to EGFR inhibitors in NSCLC is a priority in the lung cancer community. Late last year, a team at the University of California, San Francisco discovered that the protein Aurora kinase A plays a role in resistance to EGFR inhibitors. When they combined Tagrisso or Clovis’ EGFR inhibitor rociletinib with drugs that target Aurora kinase A, tumors shrank in mouse models of drug-resistant lung cancer.
Blueprint Medicines is studying a combination of Tagrisso with its RET inhibitor BLU-667 in patients with advanced EGFR-mutant NSCLC who also have RET fusions. Last year, Blueprint said that two patients in an early trial of the combo saw their tumors shrink by 78%.
Finding drugs or combinations that can target gene mutations is a challenge, because promising candidates are often crippled by the machinery inside of cancer cells, or they just can’t penetrate the cells at all. The live-cell screening system used by the University of Toronto team was designed to overcome those hurdles.
"The advantage of our method is that we are doing it in living cells, where we have all the other molecular machineries present that are important for signal transduction," said Igor Stagljar, Ph.D., professor of molecular genetics and biochemistry at the Donnelly Centre, in a statement. A pilot test of Xospata in 20 lung cancer patients with C797S mutations is now being planned.