However, nearly all non-small cell lung cancer patients eventually develop resistance to this form of treatment. While some patients develop resistance through secondary EGFR mutations that may be still vulnerable to different EGFR tyrosine kinase inhibitors, other patients develop EGFR-independent resistance where tumors no longer respond to any EGFR inhibitors. Previously, little was known about the cause of EGFR-independent resistance, and it remains challenging to treat.
A new study published in Science Translational Medicine by MD Anderson researchers identifies a key pathway driving EGFR-independent resistance and potential therapies to overcome it.
Multi-drug resistance leads to poor non-small cell lung cancer outcomes
The researchers identified activation of the yes-associated protein (YAP) and forkhead box protein M1 (FOXM1) as a key axis in EGFR inhibitor resistance and found that this pathway caused increased abundance of proteins known as spindle assembly checkpoint (SAC) components in tumor cells with EGFR-independent resistance. The researchers confirmed their findings in tumor tissue from non-small cell lung cancer patients with EGFR mutations. Tumors with high levels of FOXM1 also had high expression of SAC components, and this was associated with a worse outcome.
To determine what was causing these resistant cancer cells to no longer respond to treatment and to find out if any existing drugs could help, the team screened 1,300 drugs across a panel of EGFR inhibitor resistant lung cancer cell lines. This is one of the largest drug screens ever completed for non-small cell lung cancer.
“We found that cells that become resistant to EGFR targeting agents also have broad, multi-drug resistance,” says Monique Nilsson, Ph.D., lead author and staff scientist in Thoracic/Head and Neck Medical Oncology. “These findings correlate with the challenges our clinical colleagues see when they’re unable to successfully treat non-small cell lung cancer after it becomes resistant to EGFR inhibitors.”
The one exception the team found was a category of drugs known as spindle assembly checkpoint inhibitors. These target proteins, including Aurora kinases and PLK1. Cells that were resistant to EGFR inhibitors also expressed high levels of these SAC proteins. Furthermore, researchers revealed that the increased YAP/FOXM1 activity in the resistant cells was causing the increased expression of spindle assembly checkpoint proteins.
“Our findings showed there are vulnerabilities that can be targeted in EGFR-independent resistant NSCLC,” Nilsson says. “SAC inhibitors warrant clinical testing in patients.”
Non-small cell lung cancer clinical trials for spindle assembly checkpoint inhibitors
For patients whose lung cancer is no longer responding to EGFR tyrosine kinase inhibitors, the good news is that clinical trials for spindle assembly checkpoint inhibitors are already underway.
“This study gives us several brand new options we can test for patients whose tumors no longer respond to EGFR inhibitors,” says John Heymach, M.D., Ph.D., senior author and chair of Thoracic/Head and Neck Medical Oncology. “We were quickly able to translate these findings from the lab into the clinic. We just opened the first clinical trial testing this concept, using a combination of the EGFR inhibitor osimertinib with the aurora kinase alisertib, and started enrolling patients in the past two months. Soon we will start getting an indication if this combination appears promising.”
The research was supported by LUNGevity Foundation, Lung Cancer SPORE grant 5 P50 CA070907, MD Anderson’s Lung Cancer Moon Shot®, the National Institutes of Health (NIH) and others. A complete list of funding, along with co-authors and their disclosures is available in the paper.