Cleveland Clinic Researchers Shed New Light on Importance of Cellular Interactions in Targeted Therapy Resistance in Lung Cancer

Understanding cell growth dynamics may be the key to controlling therapeutic resistance

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New Cleveland Clinic research has uncovered key information about cellular interaction between tumor cells and normal tissue, providing better understanding of how therapeutic resistance develops.

“In the study of drug resistance, researchers often try to understand the fitness of cells that have specific mutations in the presence of a drug in a laboratory setting,” explained Jacob Scott, M.D., D.Phil., radiation oncologist and head of Cleveland Clinic’s Theory Division in the Lerner Research Institute Department of Translational Hematology and Oncology Research. “But the reality is more complex, because tumor cells don’t exist in a vacuum; instead, they co-exist in a complex, heterogeneous mixture of other tumor cells and normal tissues — an interacting ecology.”

Jacob Scott, M.D., D.Phil.

With approximately 90% of cancer deaths attributed to treatment-resistant disease, these cellular interactions, also known as “evolutionary games,” have high stakes.

In their latest study published July 1 in Science Advances, Dr. Scott and his collaborators used an assay they previously developed to directly measure those interactions in a simplified tumor environment consisting of drug-resistant non-small cell lung cancer cells and drug-sensitive precursor (ancestor) cells.  

Cells resistant to the metastatic non-small cell lung cancer treatment gefitinib were derived from existing lung cancer cells by continual treatment with gefitinib over six months, and grown in an in vitro co-culture experiment with their sensitive ancestors. Cellular growth dynamics were assessed with and without gefitinib.

“We cultured the two groups of cells together in different starting fractions and we measured how their growth changed depending on how much of each group was mixed together,” explained Jeff Maltas, Ph.D., a postdoctoral researcher at Cleveland Clinic and co-lead author on the study.

The researchers found that the fitness of the resistant type of cell changes drastically depending on the composition of the mixture. Experiments revealed that the resistant population was outcompeted by the ancestral line at all studied population frequencies in the absence of therapy, pointing to complete competitive exclusion of the resistant population and a cost of resistance.​ When gefitinib was added, there was a complete reversal of this effect, and the resistant clone was able to outcompete the sensitive ancestor.

This changing growth dynamics between treatment-resistant and treatment-sensitive cells could not be detected by standard assays available to date and suggests a novel mechanism by which resistant cells persist in the absence of treatment.

“This paper highlights the need to understand and directly measure those ecological interactions that come from being around other cell types,” Dr. Scott said. “That’s something we’re doing here that’s fundamentally different.”

Dr. Scott notes that although these latest findings cannot be directly extrapolated to clinical scenarios, they do raise important questions with potentially significant implications on clinical research and trial design. In broader terms, could patients benefit from taking a break from medication to allow the maintenance of a critical treatment-sensitive population of tumor cells? And, could treatment regimens consisting of on-treatment and off-treatment periods allow for better control of cancer cell growth and, in the long term, prolong the lives of patients?

“One of the most exciting parts of this paper is the opportunity for clinical advances that it highlights,” Dr. Scott said.  The design and testing of dynamic treatment regimens that could keep cancer cells “in check” over the long term may be the next translational application of these important findings. 

Cleveland Clinic’s Theory Division conducts cancer research to develop and make available novel diagnostic tools, targeted therapies and clinical trials for direct use in patient care.

About Cleveland Clinic
Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. Among Cleveland Clinic’s 72,500 employees worldwide are more than 5,050 salaried physicians and researchers, and 17,800 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties. Cleveland Clinic is a 6,500-bed health system that includes a 173-acre main campus near downtown Cleveland, 21 hospitals, more than 220 outpatient facilities, including locations in northeast Ohio; southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2021, there were 10.2 million total outpatient visits, 304,000 hospital admissions and observations, and 259,000 surgical cases throughout Cleveland Clinic’s health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.

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