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Lung cancers that test positive for the RET biomarker are often treated with targeted therapy. While this type of treatment has improved the duration and quality of life for many people living with lung cancer, we know that eventually these tumor cells develop drug resistance and begin to grow again. Researchers have been trying to understand what causes this drug resistance so we can develop treatment approaches to extend the time patients can effectively be treated with targeted therapies.
Two signaling pathways, involving EGFR and MET proteins, are thought to be key regulators of drug resistance. In 2022, the Hamoui Foundation, a private family foundation based in Southern California, partnered with LUNGevity to support research into understanding and overcoming drug resistance in RET-positive lung cancer.
LUNGevity spoke with one of the recipients of the Hamoui Foundation/LUNGevity Clinical Research Awards for RET-Positive Lung Cancer, Tejas Patil, MD, assistant professor of Hematology and Oncology at the University of Colorado, Denver, to learn more about this important research and how patients can get more information about his team’s clinical trial.
LUNGevity Foundation: How did your research project come about?
Dr. Tejas Patil: This project is a testament to the power of collaboration. I cannot answer this question without giving a shout-out to Drs. Lynn Heasley from the University of Colorado and Eric Haura from Moffitt Cancer Center. They have been instrumental in doing the foundational experiments that led to this study.
RET-positive lung cancer is typically treated with a targeted therapy. These therapies are initially effective, but eventually, the tumor becomes resistant to treatment and starts to grow again. Once a patient’s tumor developed drug resistance, they rebiopsied the tumor to help identify the best treatment options for the patient and then (with the patient’s permission) they studied the biopsy samples further.
They grew these resistant cancer cells in the lab and tried to understand what was causing the cancer cells to develop resistance to treatment.
LF: What was happening in these cancer cells?
TP: In some cases, it was obvious. Some tumors had a known genetic alteration, such as MET gene amplifications, and we saw an increase in MET signaling. This increase can cause the cells to grow and is likely the cause of drug resistance.
In other cases, there was no obvious mutation in the DNA we could point to as the cause of drug resistance. But when we looked in the cells, we saw the activity in the MET and EGFR signaling pathways was through the roof.
This suggested that these pathways were being activated in ways that we are not catching through comprehensive biomarker testing. Targeting MET and EGFR signaling pathways may be even more important to stopping drug resistance than we originally believed.
LF: Please tell us more about your research project.
TP: Our goals are two-fold. First, we’d like to improve our testing approaches so that we can accurately identify patients who have drug resistance caused by rogue EGFR and MET signaling.
Second, we aim to target both the MET and EGFR signaling pathways to stop drug resistance in RET-positive lung cancer. In this study, we are using amivantamab, an FDA-approved drug for treating lung cancer with EGFR exon 20 insertion mutations. It is part of an exciting class of drugs called bi-specific antibodies—molecules designed to bind and act on two different proteins. In this case, the drug is acting on EGFR and MET.
LF: Why is this work exciting for patients?
TP: We are hopeful that this work will give us new insights into drug resistance which will be beneficial for anyone with a lung cancer diagnosis. In addition, we know drug resistance involving EGFR and MET signaling pathways have also been identified in tumors with ALK and ROS-1 driver mutations. This suggests our research could be directly applicable to patients with these types of lung cancer as well.
LF: Is this clinical trial available to patients?
TP: This clinical trial is now open at the University of Colorado and the University of Michigan. We’re looking for patients who have lung cancer with ALK, RET or ROS-1 biomarkers. Patients who have been treated with a targeted therapy and whose tumors have started growing again, may be eligible to enroll in our clinical trial and receive this treatment.
Learn more about this clinical trial.
LF: Why is it important to continue supporting lung cancer research?
TP: We’ve seen major improvements in the way we treat lung cancer over the past 20 years. However, there are still major unmet needs in terms of improving the cure rate and long-term survival rates for patients.
LF: How has this award impacted your research?
TP: Research is a team sport. This award has not only helped me in my career personally, but it’s also set up lifelong relationships with other colleagues who can also help us deliver on the promise of improving therapeutic options for people who have been affected by lung cancer.
If you have a known biomarker, visit the LUNGevity Patient Gateways for more research updates about your specific type of lung cancer.