The importance of cellular interactions for treatment-resistant cancer cells has been revealed

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

“In studying drug resistance, researchers often try to understand the fitness of cells that have specific mutations in the presence of a drug in the laboratory,” he explained. Jacob Scott, M.D., Ph.D.radiation oncologist and head of the Cleveland Clinic Theoretical department in the Division of Translational Hematology and Oncology Research at the Lerner Research Institute. “But the reality is more complicated because tumor cells do not exist in a vacuum; instead, they coexist in a complex, heterogeneous mixture of other tumor cells and normal tissues—an interacting ecology.

Since approximately 90% of cancer deaths are due to drug-resistant diseases, these cellular interactions, also known as “evolutionary games,” have high stakes.

In their latest study, published on DATE in Scientific progressDr. Scott and his associates used analysis they were previously developed to directly measure these interactions in a simplified tumor environment consisting of drug-resistant non-small cell lung cancer cells and drug-sensitive precursor (progenitor) cells.

Treatment-resistant cells in metastatic non-small cell lung cancer gefitinib were derived from existing lung cancer cells by long-term treatment with gefitinib for six months and grown in IVF a joint cultural experiment with their sentient ancestors. Cell growth dynamics were assessed with and without gefitinib.

“We cultured the two groups of cells together in different starting fractions and 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. of the study.

The researchers found that the fitness of the resistant cell type changed dramatically depending on the composition of the mixture. Experiments revealed that the resistant population was displaced from the lineage at all population frequencies examined in the absence of therapy, indicating complete competitive exclusion of the resistant population and the cost of resistance. When gefitinib was added, there was a complete reversal of this effect and the resistant clone succeeded to overtake the sentient progenitor.

This changing growth dynamics between treatment-resistant and treatment-sensitive cells cannot 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 these ecological interactions that come from being around other types of cells,” said Dr. Scott. “It’s something we’re doing here, and it’s fundamentally different.”

Dr. Scott notes that although these latest findings cannot be directly extrapolated to clinical scenarios, they raise important questions with potentially significant implications for clinical research and trial design. More generally, could patients benefit from treatment interruption to allow the maintenance of a critical treatment-sensitive population of tumor cells? And do treatment regimens consisting of periods of treatment and periods without treatment 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 advancement it highlights,” said Dr. Scott. Designing and testing dynamic treatment regimens that could keep cancer cells “in check” in the long term may be the next translational application of these important findings.

Cleveland Clinic’s theoretical division conducts cancer research to develop and deliver new diagnostic tools, targeted therapies and clinical trials for direct use in patient care.

Reference: Farrokhian N, Maltas J, Dinh M, et al. Measuring competitive exclusion in non-small cell lung cancer. Sci Adv. 2022;8(26):eabm7212. doi: 10.1126/sciadv.abm7212

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