The development of resistance to diseases such as cancer and infectious illnesses presents a significant challenge.
Contrary to the belief that mutations causing resistance would decline without treatment due to slower growth, preexisting resistance is prevalent in evolving diseases like cancer and pathogens, going against traditional assumptions.
In the case of cancer, it is widely recognized that even before treatment, a small number of drug-resistant cells likely exist in tumors. Interestingly, these mutant cells are known to have lower fitness than the surrounding ancestor cells prior to treatment, raising the question of why these less fit cells survive.
In a recent study, researchers at Case Western Reserve University and Cleveland Clinic made an intriguing discovery: the interactions between these mutant cells and their ancestors, akin to different species in an ecosystem, could hold the key to understanding this scenario.
Their findings propose that these ecological interactions play a crucial role in mitigating the drawbacks of resistance, offering a pathway for the survival of preexisting resistance, not only in lung cancer but in various medical contexts where drug resistance is a concern, spanning different cancers, pathogens, and parasites.
The Study
Using a combination of computer simulations and analytical findings, the study introduces a mathematical framework to explore how these ecological interactions impact the evolutionary dynamics of resistance.
“This discovery is incredibly significant as it resolves fundamental disagreements between classical population genetics and theoretical ecology,” stated the study’s lead researcher Jacob Scott, who serves as a staff physician-scientist at Cleveland Clinic, an associate professor of physics and medicine at Case Western Reserve, and the associate director for data science at the Case Comprehensive Cancer Center.
The study also emphasizes the practical implications of these results by genetically modifying common resistance mechanisms identified in non-small-cell lung cancer, a disease known for its existing resistance to targeted therapies and the primary cause of cancer-related deaths in the US.
Each genetically altered cancer cell line exhibited advantages when paired with its ancestor during the group’s evolutionary game assay when cultured alongside their treatment-sensitive ancestor, aligning with the new theory and resolving the paradox.
“Our findings propose a compelling new theory for the prevalence of treatment resistance: resistant cells are preserved by the surrounding cells through an ecological mechanism,” stated Jeff Maltas, the lead author of the study and a post-doctoral fellow at Case Western Reserve. “These outcomes introduce a novel treatment approach: creating treatments that disrupt the ecological interaction enabling resistance, rather than developing new drugs for increasingly resistant populations.”
This interdisciplinary research, encompassing physics, genetics, theoretical ecology, and mathematical oncology, published in PRX Life, marks a significant advancement in understanding the evolution of resistance. The researchers hope it could lead to innovative strategies for combating cancer and infectious diseases.
