- In order to work, drug molecules need to fit snugly within pockets called binding sites on cancer cell proteins.
- A new paper by Dana-Farber scientists suggests that a strategy of targeting two binding sites, rather than one, can exert a powerful stranglehold on cancer-related proteins.
- In laboratory and animal studies of a form of lung cancer, the combination impeded tumor cell growth and increased tumor cell death more effectively than either drug alone.
Medically reviewed by Pasi A Jänne, MD, PhD
Imagine inserting a key to shut off an engine only to find that it no longer fits — that the configuration of the lock has been changed without notice. Scientists developing targeted therapies to treat cancer often face a similar conundrum.
Targeted therapies derive their effectiveness from an exquisite precision: to work, drug molecules need to fit snugly within pockets called binding sites on cancer cell proteins. The binding hinders the protein from driving tumor cell growth. But cancer’s capriciousness —its tendency to acquire additional genetic mutations — can alter the contours of the binding site itself, so the drug no longer fits there as well. The result can be a tumor that grows in spite of treatment: a drug-resistant cancer.
A new paper by Dana-Farber scientists suggests that a strategy of targeting two binding sites, rather than one, can exert a powerful stranglehold on cancer-related proteins. In laboratory and animal studies of a form of lung cancer, the combination impeded tumor cell growth and increased tumor cell death more effectively than either drug alone — raising the promise of longer remissions.
Targeting EGFR gene mutations
The study, published in Cancer Discovery, focused on non-small cell lung cancer (NSCLC) that carries a mutation in the gene EGFR. Such EGFR mutants constitute 10-30% of all cases of NSCLC, which itself is the most common form of lung cancer.
“In NSCLC, a mutation in EGFR has an activating effect: it ‘switches on’ the EGFR protein to drive cancer cell growth,” says Pasi A Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology and the Belfer Center for Applied Cancer Science at Dana-Farber Cancer Institute. Jänne is co-senior author of the paper with Dana-Farber colleagues Michael Eck, MD, PhD, and Nathanael Gray, PhD.
“Drugs that inhibit EGFR have been remarkably successful, but resistance inevitably arises in about a year. In 60 percent of patients, resistance is due to the emergence of a new mutation in EGFR, called T790M,” Jänne says.
Last year, the U.S. Food and Drug Administration approved the drug osimertinib, which, unlike earlier agents, targets only mutant forms of EGFR, not the normal form. In patients who become resistant to other drugs because of the T790M mutation, osmertinib often provides a substantial benefit: their progression-free survival — how long they lived without the disease worsening — was 9.9 to 12.3 months in one study. Eventually, the disease can become resistant to osimertinib as well, when new EGFR mutations arise.
The mutations that render NSCLC resistant to osimertinib and its kin all alter the binding site of the EGFR protein. A drug molecule that binds to a different site — one unaffected by these mutations — may offer a way to slow or prevent resistance. The site, known as the allosteric site, occupies a separate portion of the EGFR protein and serves as a kind of secondary on-off switch for the protein’s activity.
In a 2016 paper, Michael Eck provided the first demonstration that it’s possible to create a molecule that blocks the allosteric site. For the current study, Nathanael Gray and his associates developed such an inhibitor, called JBJ-04-125-02.
Jänne and his colleagues tested the new inhibitor in NSCLC that carried several mutations affecting the binding site – the original mutation, the T790M mutation, and a follow-on mutation called C797S. In both laboratory cell lines and animal models of the cancer, the drug slowed tumor cell proliferation and impaired EGFR’s ability to signal cell growth.
Unfortunately, the inhibitor’s effectiveness was eroded by EGFR’s tendency to form a dimer — a complex consisting of two identical EGFR proteins. The positioning of the two proteins within the complex made the allosteric sites less accessible to the drug. Once again, the disease seemed to have found a loophole through which drug resistance can emerge.
It turns out, however, that osimertinib — uniquely among EGFR inhibitors — boosts JBJ-04-125-02’s binding to the allosteric site. A combination of the two drugs braked cancer cell growth and spurred cancer cell death to a greater degree than either agent alone.
“Our findings suggest that drug combinations that target both the binding site and the allosteric site in patients with lung cancer carrying an EGFR mutation may be especially effective,” Jänne remarks. “This study is an excellent example of how research that engages different specialties — chemistry, structural biology, and laboratory testing — can unite to advance treatment for a disease.”