Drugs that focus on specific mutations in tumors — known as targeted therapies — are an increasingly important part of treatment for many cancers, because they don’t cause many of the side effects associated with traditional therapies. But like most other cancer drugs, these targeted treatments have an unfortunate drawback: They may eventually stop working as tumors grow resistant to them.
For certain head and neck cancers, such as those that form in the mucus lining inside the nose, mouth, and throat, a class of targeted drugs called EGFR inhibitors are often given either alone or with radiation therapy or chemotherapy. Their benefit is usually minimal and short lived, however.
Now a new study from Memorial Sloan Kettering scientists suggests that combining these drugs with another, experimental class of targeted drugs called PI3K inhibitors may lead to a longer-lasting, more durable response.
The study also suggests that this combination may be effective against a common type of esophageal cancer, which currently has few good treatment options and low long-term survival rates.
Uncovering the Methods of Resistance
“It’s important to dissect the molecular mechanisms of how tumors develop and change, so that we can better understand how to treat them with drugs,” explains Maurizio Scaltriti, a cancer biologist who is co-director of the laboratory of MSK Physician-in-Chief José Baselga and one of the senior authors of the new study, along with Dr. Baselga. “This knowledge might inform the development of new drug combinations to control drug-resistant tumors.”
Until now, much of the research done by Dr. Baselga’s lab has focused on targeted therapies for breast cancer, including PI3K inhibitors. A recent study of breast cancer patients treated with a PI3K inhibitor called BYL719 provided new insights into how breast tumors develop resistance to that drug — but not all cancers develop resistance by the same mechanism.Back to top
Targeting Squamous Cell Carcinomas
“In the first human trial of BYL719, results showed that, in addition to breast cancer, head and neck cancers called squamous cell carcinomas (SCCs) were also sensitive to the drug,” Dr. Scaltriti explains. “We knew that this drug was going to be used for these head and neck tumors, and therefore our aim was trying to predict which mechanism of resistance the tumor would use to get rid of the drug’s inhibitory effect.”
The investigators tried to predict how the cancer would develop resistance to the targeted drug.
In the current study, which was published in the journal Cancer Cell, the investigators studied several cell lines of SCC head and neck tumors. They also included SCC esophageal tumor cell lines. “These two types of cancer have similar morphological characteristics, and similar molecular characteristics as well,” he notes.
Over several months, the investigators treated the cell lines with increasingly high doses of BYL719, until they were able to generate cells that were resistant to the drug. They then analyzed these drug-resistant cell lines to determine how they differed on a molecular level.
By studying the gene expression activity within the cells, the team found a common thread: A protein called AXL was overexpressed, which means that it was found at high levels in the cells that became resistant to the drug. Importantly, this was also confirmed in samples from head and neck cancer patients treated with BYL719. The researchers then showed how this situation ultimately resulted in the cells’ ability to acquire resistance to BYL719.Back to top
Advancing a Combination Therapy
Next, the researchers showed that AXL was sending signals through the protein EGFR, and demonstrated that EGFR inhibitors were able to kill the tumor cells that had become resistant to PI3K inhibitors. Several EGFR inhibitors are already used for the treatment of SCC head and neck cancers.
Clinical trials are already under way to test the drug combination in patients with head and neck cancers.
“If you treat head and neck cancer with a PI3K inhibitor or an EGFR inhibitor alone, some of them will find a way to escape the drug’s effect. But if you co-inhibit the tumors with both types of drug, you are more likely to achieve a better effect and to delay or even prevent the emergence of drug-resistant tumor cells,” Dr. Scaltriti concludes.
MSK is currently enrolling patients in a clinical trial to test PI3K inhibitors and EGFR inhibitors together in patients with head and neck SCCs. An international phase II clinical trial is already ongoing, with promising preliminary results. MSK has also started another clinical trial testing this drug combination together with radiation therapy, a common component of treatment for head and neck cancer.Back to top