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BRAF is an important signaling protein that regulates how normal cells grow and multiply through the MAPK (mitogen activated protein kinase) signaling pathway. However, changes in the BRAF gene can cause the cells to grow unchecked and develop into a tumor. This can lead to many types of cancer, including melanoma, colorectal, thyroid, and lung cancers. Researchers estimate that 4%-15% of tumors, from all types of cancer, are driven by changes in the BRAF gene.
In lung cancer, approximately 1%-2% of non-small cell lung cancers (NSCLCs) have changes in the BRAF gene. These changes have been grouped into three classes.
- Class 1 has V600 mutations. BRAF proteins with these mutations are known to have significant kinase activity. The most common one is the BRAF V600E mutation. There are currently two FDA-approved combinations for this class of mutations.
- Class 2 includes several alterations, including fusions (where two proteins are joined together), with moderate to high kinase activity.
- Class 3 has mutations in key areas which lead to limited kinase activity.
Currently, there are no targeted treatments for class 2 BRAF fusions in lung cancer. These fusions represent an important opportunity to build our knowledge base and provide life-saving treatment options for people living with this lung cancer subtype.
To support research into this important space, LUNGevity awarded one of our 2022 Career Development Awards to Michael Offin, MD, a physician-scientist at Memorial Sloan Kettering Cancer Center to quickly bring new treatment options to patients living with NSCLC with BRAF fusions.
We caught up with Dr. Offin to learn about this research, the impact of this award, and his perspective on the importance of supporting lung cancer research.
LUNGevity Foundation: How did you become interested in studying BRAF fusions in lung cancer?
Dr. Michael Offin: I had a patient with EGFR-positive lung cancer whose tumor developed a BRAF fusion mutation during treatment. I wanted to know how best to help this patient, so I turned to the scientific literature and saw an unmet need. BRAF co-mutations are not very common, but they do happen. Unfortunately, there is not enough known to fully optimize treatment for these patients.
Working with a collaborator, we saw that we had to go back to the basic sciences to first learn about treating these BRAF fusions by themselves. Once we understand how to treat them on their own, we can develop better treatments for patients who have BRAF co-mutations.
LF: Explain your LUNGevity-funded research project?
MO: We are testing small molecule inhibitors and other types of drugs that target BRAF fusions to determine the most effective drug that can move forward to a phase 1 clinical trial. We also are creating lab models from tissue samples (donated by patients) to help us explore and develop new therapies for people with cancer driven by BRAF fusions.
LF: Why is this research exciting for the lung cancer community?
MO: In general, for every fusion protein we have tried to target, people initially say it is not possible. It’s too rare. That's what initially happened with NTRK and NRG1 and now we have targeted treatments. How did that happen? Somebody pushed for it. Someone was willing to look for a treatment. Sure, these mutations are uncommon. But for patients who have them, this work is important.
I am not interested in creating models that are only for lab work. That is why we are focused on testing drugs that we can get to patients. We’re making sure whatever compound we are testing has a path to get to the clinic and help people.
LF: How has the LUNGevity award impacted your career?
MO: The research grant from LUNGevity was instrumental in my career.
As a junior faculty member, the LUNGevity’s Career Development Award was a key step in my academic development. It gave me the protected time I needed to focus on my research and build a portfolio of work that led to a larger grant from the US Department of Defense.
LF: What would you say to people considering supporting lung cancer research?
MO: It is always a kind thing to donate to research. You are helping others, their families, and potentially yourself or your own family in the long term.
Several years ago, I wrote a research paper that was entirely based on tissue samples from one patient. When she passed away, she donated her body to research. While it is impossible to truly thank her and her family, I made sure to acknowledge her in the paper.
It’s important to understand that your contributions—whether they are tissue samples or financial—help us do important things. It is a responsibility we take seriously. We ensure they are used for the right things to move the lung cancer science forward so we can build a world where no one dies from lung cancer.
Additional reading:
- Research paper with an excellent diagram explaining the differences in activity in the 3 classes of BRAF alterations.
- Research paper discussing basic science of the 3 classes
- Research paper demonstrating progress in understanding how to treat BRAF fusions