For years, the Gray Lab has focused on a major challenge in lung cancer treatment: how to sustain the effectiveness of one of the most effective targeted therapies for patients in the long term.
Led by Stanford Cancer Institute Associate Director for Cancer Drug Discovery Nathanael Gray, PhD, Krishnan-Shah Family Professor of Chemical and Systems Biology, the lab’s work centers on epidermal growth factor receptors (EGFR). EGFR is a protein that sits on the surface of many cells and helps regulate cell growth and division. In some lung cancers, particularly non–small cell lung cancer (NSCLC), EGFR becomes mutated. When this happens, the receptor is stuck in the “on” position, pushing cancer cells to grow uncontrollably, a hallmark of cancer.
The unmet need
NSCLC is the most common type of lung cancer, accounting for approximately 85% of cases, and typically grows and spreads more slowly than small-cell lung cancer. It develops when the lungs’ epithelial cells grow uncontrollably. These specialized cells line the entire respiratory tract as a crucial barrier against inhaled pathogens, allergens, and toxins. They regulate fluid balance, produce mucus, and initiate immune responses, all of which are essential for healthy lungs.
EGFR-mutated NSCLC is a subtype often found in non-smokers, women, and patients of Asian ethnicity with adenocarcinoma, an often aggressive type of cancer that develops in the glandular epithelial cells lining organs. This mutation subtype accounts for about 10-15% of NSCLC in the United States and up to 50% of cases in Asian populations. It’s primarily treated with EGFR inhibitors, a type of targeted therapy that blocks the EGFR signaling pathway, stopping cancer cells from receiving signals to grow, divide, and survive, effectively halting tumor proliferation and metastasis.
More than a decade ago, the lab helped create an early experimental compound known as WZ4002, an EGFR inhibitor designed to target the drug-resistant T790M mutation in NSCLC. This compound is considered the predecessor of osimertinib, as it was the first third-generation compound to successfully target the T790M mutation while sparing healthy cells, demonstrating that a specific chemical sequence could bypass the resistance pathways that previous drugs could not. Historically, first and second-generation drugs for this disease would eventually fail because of the developed resistance mutation.
Today, osimertanib is one of the leading treatments for EGFR-mutated NSCLC worldwide. It binds to a specific spot on the EGFR protein to block its cancer-driving activity. Many patients respond extremely well at first, but over time, the cancer can find a way around the drug and begin to grow again, sometimes after one to three years.
“Patients will typically respond very well to osimertinib, but then they get resistant,” Gray explained. “So we’ve been coming up with other ways to re-inhibit EGFR.”
The lab has a three-fold strategy to approach this problem.
Strategy 1: Destroying EGFR instead of blocking it
If blocking the protein’s function becomes ineffective, Gray wondered whether they could just eliminate the protein entirely.
“If you can’t unlock the lock, you can blow it up,” he said.
The lab developed a new EGFR degrader, a class of drug that triggers EGFR’s destruction inside the cancer cell.
Strategy 2: Targeting a new control switch with allosteric inhibitors
ATP is the main energy-carrying molecule inside cells. It binds to a specific site and catalyzes downstream reactions, such as cellular growth. Traditional EGFR drugs, including osimertinib, bind to the ATP site and prevent the receptor from signaling to promote cell growth. But cancer often mutates the ATP site, preventing drugs from latching on.
To overcome this, the lab developed allosteric inhibitors that bind to an alternative binding pocket and inhibit the enzyme in a different manner.
Strategy 3: A “molecular bidentate” that grips EGFR in two places
The team’s newest approach aims to make it even harder for EGFR to escape.
Osimertinib is a covalent inhibitor, meaning it forms a strong chemical bond with a single site on the EGFR protein. To make the drug stronger, the lab designed a compound that can form two bonds to EGFR, creating an irreversible covalent bond. By permanently "plugging" the pocket, osimertinib prevents ATP from binding, which halts the downstream signaling that drives cancer cell proliferation.
“Osimertinib grabs onto EGFR at one residue,” Gray explained. “We found out how to grab onto two residues at the same time. That makes it much harder for the enzyme to escape the grip of the drug.”
This dual-gripping design, which Gray calls a molecular bidentate, is currently being evaluated and refined to create a version that can be brought to patients.
What comes next
Across all three approaches, the goal remains the same: to stay one step ahead of drug resistance and give patients with EGFR-mutated lung cancer more effective treatment options.
It’s complicated, but at the end of the day, it’s just about trying to find the causes of cancer and using it to find cures. The patients need these drugs now."
“It’s complicated, but at the end of the day, it’s just about trying to find the causes of cancer and using it to find cures. The patients need these drugs now,” Gray said.
