Cancer researchers have long been interested in the resistance that lung cancer patients develop to targeted therapies aimed at specific mutations. Though the therapies provide significant remission at first, the cancer eventually finds a way to return.
A related but less studied phenomenon in lung cancer is that of “persister cells” — cancer cells that never respond to targeted therapies and are still visible on scans even after treatment has begun. Though persister cells are dormant at first, they can eventually adapt to therapy and spawn cancer cells that are highly resistant to anticancer treatment.
The role of MET
Thanks to a grant from the Gilead Sciences Research Scholars Program, University of Colorado Cancer Center member Tejas Patil, MD, is launching a study to better understand how persister cells survive in the presence of targeted therapy and what methods might be used to target them to improve patient survival.
“Our thought is that these cancer cells that are still hanging around on the scans likely have some kind of adaptation that is allowing them to survive in the presence of the drug,” says Patil, assistant professor of medical oncology. “We’re really interested in understanding what’s happening on a single-cell level with those cancer cells. We’re specifically interested in a signaling pathway called the MET pathway and how that may play a role in allowing these cells to survive in the presence of targeted therapy.”
Using RNA sequencing and spatial multiomics, Patil and his team will compare tissue samples taken when the patient is first diagnosed and at eight weeks after treatment begins. They will be looking for increased expression of the MET protein, as well as increased expression of other proteins that could be targeted to eliminate persister cells.
“RNA sequencing will allow us to analyze the genomic profile of the tumor and try to understand what pathways are getting turned on or turned off at the eight-week time point,” he says. “Spatial multiomics involves looking at tissue under a high-resolution microscope at the single-cell level, so you can see what each individual cancer cell was doing at that moment. The downstream hope is that we find some kind of signal, either within the MET pathway or some other pathway, that can allow us to add in a therapy or come up with a novel clinical trial design that hits these cancer cells hard at the very beginning of the patient's journey.”
Practical timing
Though treatment-related changes are visible as soon as two weeks after therapy begins, Patil chose the eight-week time period as a matter of practicality — it’s the point at which patients typically receive their first scan to see how the treatment is working.
“It’s very hard for patients to consent to a tissue biopsy at two weeks,” he says. “It's very challenging, mostly because of the psychological component of having a new stage 4 lung cancer diagnosis and then having to get another biopsy two weeks after you start treatment. Usually by eight weeks, most patients will be getting a treatment scan. We felt that would line up better with what actually happens in real practice, versus having a patient come in for a biopsy at a somewhat arbitrary time point.”
Improving outcomes
MET is a common pathway used by cancer cells to escape the effects of treatment. That history gives Patil confidence that MET is also being used by persister cells to avoid those effects altogether. If his hypothesis is correct, a MET inhibitor, given early in the treatment process, can destroy persister cells and prevent them from contributing to treatment resistance down the line.
“If everything goes according to plan and our results pan out the way we expect, we can look at developing a consolidation strategy,” he says. “If MET is highly activated eight weeks after therapy begins, we can think about adding in a MET inhibitor for a brief period to try to kill the persister cell population as best as possible. Hopefully that approach will allow a patient to remain on their targeted therapy for even longer.”
Patil says he is grateful for the award from the Gilead Sciences Research Scholars Program — administered by the biopharmaceutical company Gilead Sciences — that will allow him to develop tools to conduct his research.
“This is a fantastic award that will allow us to start asking important questions about these persister cell populations and seeing if there are any therapeutic vulnerabilities we can potentially target,” he says. “It gives us a platform to analyze these data and allows us to put a protocol in place to do these early biopsies. I'm hopeful that the results will inform future directions of research and start me off on a productive career where I'm asking a bunch of important questions on this topic. I'm really honored to receive it.”
