Studying Drug Resistance From a New Angle

Juhi Kunde, MA, LUNGevity Science Writer

The development of “targeted therapies” which block the function of mutant proteins within tumor cells has revolutionized the treatment landscape for many cancers, most of all lung cancer. EGFR is one such protein which is often altered (mutated) in lung cancers. Over the past decade, multiple EGFR targeted therapies have been developed, with each generation of drugs becoming increasingly potent.

At present, patients with advanced EGFR-mutated lung cancer are treated with osimertinib (Tagrisso®), the latest and most effective FDA-approved EGFR targeted therapy to date. Unfortunately, despite high response rates and often dramatic tumor shrinkage, over time, the tumor cells eventually develop drug resistance by finding a way to circumvent the effects of osimertinib. This allows the cancer to progress. Innovative treatment strategies are needed to help patients who experience cancer progression while receiving osimertinib therapy.

Christine M. Lovly, MD, PhD, Associate Professor of Medicine and co-leader of the Translational Research and Interventional Oncology Research Program at the Vanderbilt-Ingram Cancer Center and member of LUNGevity’s Scientific Advisory Board, understands the urgency behind this need.

Dr. Lovly is a physician and scientist whose focus is on trying to improve treatment strategies for patients with lung cancer. She collaborates closely with a remarkable group of patients advocating for their own life-saving research – the EGFR Resisters. The EGFR Resisters is a grassroots patient-driven community dedicated exclusively to changing EGFR-positive lung cancer into a manageable, chronic disease. “It is very special to be able to partner with these patients. We’ve become close professionally and personally. It’s like working with friends,” notes Dr. Lovly.

With the help of an EGFR Resisters/LUNGevity Foundation research award (funded by the EGFR Resisters), Dr. Lovly is taking a step back to look at this problem of drug resistance from a new angle. “If we treat a patient and see 50% tumor shrinkage, we usually celebrate it as a win. But there is still 50% left behind that needs to be understood and treated!” she notes. “We urgently need to find ways to increase our drug effectiveness, so that 50% tumor shrinkage becomes 100%”.

One of the big reasons that researchers haven’t been able to address this issue, is that the technology wasn’t sophisticated enough to study individual tumor cell responses in patients undergoing treatment. But now it is.

Dr. Lovly and her team of expert investigators from renowned cancer centers are trying to understand the molecular basis of drug resistance and develop ways to block drug resistance before it begins. The team is working with drug-tolerant persistor cells (DTPCs), the tumor cells that remain after the patient’s best response to osimertinib; they are studying them in the laboratory using single-cell biology techniques. “The ultimate goals of this work are to expand our understanding of DPTCs and drug resistance and to develop treatments that can turn a partial shrinkage of an EGFR-mutated tumor into a complete tumor regression.”

This groundbreaking work will take time to complete, but the results have the potential to change the way we treat EGFR-mutated lung cancer and possibly the way we approach all types of lung cancer.

In the meantime, there is a lot that patients and their loved ones can do to help support this type of cutting-edge research. “Many researchers like to have patients visit their laboratory and see the work being done. Once COVID protocols relax, see if you can visit a lab to learn first-hand what is being studied,” suggests Dr. Lovly. “As a patient or caregiver, another way to support research is to ask your doctor about clinical trials, which are the vehicle whereby cutting-edge therapies are brought to patients.  

In addition, to conducting this laboratory bench-to-bedside research, Dr. Lovly’s team is working to train the next generation of lung cancer researchers. “It’s so important that we have a robust and diverse pipeline of researchers in place to continue to advance lung cancer studies,” she says.

“With smart, fresh, scientific minds, new technologies and the support of our patient communities, we are poised to make big improvements to the care and treatment of lung cancer patients,” notes Dr. Lovly, “As we continue to collaborate, we move closer to the future where no one dies from lung cancer.”