Advances in targeted therapies have allowed us to treat some types of lung cancer with mutations in specific genes (for example, EGFR, KRAS, and RET). This has given some patients with lung cancer a better quality of life and longer survival. However, even after an initial response to the targeted therapy, lung tumors will eventually grow again. Research suggests this drug resistance is likely to involve drug-tolerant persister cells, or DTPCs—cells that tolerate the drug and persist after treatment. DTPCs pose a major challenge for treating many types of cancers, including lung cancer.
To explore new approaches for addressing drug resistance, RETpositive, a patient-led advocacy group, partnered with LUNGevity to award Hideo Watanabe, MD, PhD, associate professor of Medicine at the Icahn School of Medicine at Mount Sinai, one of the RETpositive/LUNGevity Foundation Lung Cancer Research Awards in 2022.
LUNGevity spoke with Dr. Watanabe to understand his novel approach to ending drug resistance in RET-positive lung cancer and the importance of basic science research.
LUNGevity Foundation: How did you become interested in lung cancer?
Dr. Hideo Watanabe: I started my career as a pulmonologist in Japan where we have a different medical system. In the US, medical oncologists treat patients with cancer of different organs. In Japan, doctors have an organ specialty and they treat all the diseases related to that organ. So, as a pulmonologist in Japan, I treated everything from asthma to lung cancer.
I found it very fulfilling to work with all my patients, but particularly those with lung cancer. At the time, the treatment options available for patients were mostly limited to surgery, radiation, and chemotherapy. I had the honor of really getting to know my patients, listening to them reflect on their lives, and understanding their unique needs.
LF: Tell us about the research you do in your lab.
HW: Approximately 20 years ago, when I was working to identify my research focus, the first targeted therapy for lung cancer became available for patients with EGFR-positive lung cancer. I wanted to understand more about this new field. So, I did a postdoctoral fellowship at the Dana-Farber Cancer Institute with Dr. Matthew Meyerson, one of the researchers who first discovered EGFR mutations in lung cancer.
While I was there, I was working to find other important mutations or changes that we could leverage to treat the disease. My findings suggested that proteins known to be involved in the normal lung development of embryos could also be important for lung cancer development in adults.
Today, my lab is focused on studying these protein pathways to understand the basic mechanisms underlying lung cancer development. The more we understand about how and why it develops, the more effective we can be at treating it.
LF: Why is basic science important for the lung cancer community?
HW: Often it feels like the discoveries happen out of the blue. The way we talk about things, it sounds like a researcher conducts a clinical trial and suddenly, we have a new way to treat a disease. But the reality is that basic science research, or curiosity-driven research, builds up the knowledge base so we can conduct that clinical trial. It’s important to encourage scientists to explore many different areas and learn all we can about lung cancer from many different angles. This is how we can find those key connections and accurately interpret clinical trial results to create effective new treatments down the road.
LF: How did your basic science lab end up working on a treatment for drug resistance in RET-positive lung cancer?
HW: A postdoctoral fellow in my lab came up with the idea for this area of study. In our lab, we were mostly focused on understanding the underlying mechanisms of lung cancer development. She was interested in creating therapeutic options for patients. We focused our efforts on two signaling pathways—Wnt and Hippo—that are needed for normal development. These pathways can go rogue in cancer cells. We had a hunch that they may play an important role in how DTPCs adapt to the drugs in their environment and begin to grow again. It turned out to be an exciting field of study.
We are grateful for the RETpositive/LUNGevity research award because it allows us to expand our research to study these protein pathways in RET-positive lung cancer. This is part of the power of patient advocacy groups.
LF: Please describe the project funded by RETpositive and LUNGevity.
HW: Patients often respond well to RET targeted therapy (such as tyrosine kinase inhibitors, or TKIs) initially. However, as with all TKI treatments, the RET-positive lung cancers will eventually become resistant to these drugs and start to grow again.
This project will test a new approach to block DTPCs from growing and hopefully prevent cancer relapse.
LF: Has this award been impactful for your research lab?
HW: This award, along with all LUNGevity’s research awards, are seeds for change. They allow us to try new things that are scientifically exciting and synergize with our expertise in the areas we already focus on. I am very grateful for this opportunity to expand our impact within the lung cancer community.