Despite a favorable initial response to therapy, a third of cancer patients will develop recurrent disease and succumb within five years of diagnosis. It is widely accepted that relapse can be driven by genetic mutations that were either pre-existing or arose de-novo during drug treatment. Over the last decade a rare subpopulation of cells, termed cancer persister cells, have been identified as orthogonal drivers of treatment failure. Unlike resistant cells that harbor a genetic alteration that enables them to survive and expand in the presence of a drug, persister cells are transiently drug-tolerant cells that can survive exposure to therapy through reversible, non-mutational mechanisms. The nascent field of cancer persistence has expanded rapidly since the first cancer persister system was reported 12 years ago. Initially described in the context of targeted therapy, drug-tolerant cancer cells have since been implicated in disease recurrence in multiple cancer models and in response to a diverse array of treatments.

This Forbeck forum will provide a unique opportunity for investigators from around the world who are working on this newly emerging field in cancer to gather, discuss, and critically examine emerging concepts in the field of cancer persisters. We will start with understanding molecular mechanisms of cancer persistence and will continue with discovering therapeutic targets of persistent cells, deciphering their heterogeneity at single cell level, learning how cancer persisters differ from microbial persisters, modeling of the dynamics of persistent cells, and identifying contribution of immune escape mechanisms in driving cancer persisters. This meeting will bring together researchers who study non-genetic drug tolerance in various contexts and who are not used to interacting with each other to discuss key questions in the field and lay the foundations for generating a community dedicated for the study of nongenetic tolerance/resistance. We anticipate that this will result in potential collaborative projects, ideas for sharing the concepts discussed in the meeting with the greater scientific community through publications, and aspirations for future follow-up meetings focused at this exciting emerging field.

The most important factor that limits the success of anti-cancer therapy is the emergence of drug resistance; for instance, median survival of 30-36 months with vemurafenib in BRAFmutant melanoma yet > 1/3rd of patients die within 2 years. Until recently, most of the studies to date (as well as most conferences) were focused on studying the contribution of genetic mechanisms of evolution in drug resistance. However, we seem to have reached a limit in terms of characterizing genetic mutations that give rise to acquired resistance across multiple cancer types. It has become clear from numerous lines of recent evidence that beyond genetics, nongenetic/functional mechanisms that also contribute to resistance development. Similar to bacterial cells in response to antibiotic resistance, cancer cells also acquire a persister state to escape drug pressure. The emergence of persister population can occur via different mechanisms including epigenetic plasticity, metabolic reprogramming, itochondrial unpriming, immune escape, and others at bulk and single-cell levels. Despite important similarities in, and differences between, mechanisms of drug tolerance in bacteria and in cancer cells, few opportunities exist for leaders in these two related fields to interact in a meaningful way. Therefore, this meeting could provide a unique opportunity to gather experts working on microbial and cancer persistence, to define phenotypes, emergent mechanisms, and targeting strategies to overcome non-genetic resistance mechanisms.

The goal of this meeting is to bring together experts from fields of epigenetics, metabolism, single cell omics and microbial and cancer persisters fields to facilitate the discussion to define the functional phenotype of cancer persisters, discuss innovative models to study persisters, and devise novel strategies to target this rare minimal disease (MRD)like cells. By bringing clinicians and translational biologists together, we hope to come up with studies that can provide strong clinical evidence of the xistence of persister population across different tumor types and discuss ways to target it to prevent disease recurrence. This meeting will bring together biologists, bacteriologists, translational scientists, and clinicians to discuss emerging concepts in the non-genetic cancer resistance field and lay the foundation for a cohesive framework to study them. This meeting will provide a unique opportunity to create the intellectual infrastructure and common ground that is needed to propel the field forward. For the first time, this forum will also provide a unique opportunity to bring together scientists from cancer persistence and microbial persistence fields and enable interdisciplinary discussions on how lessons from antimicrobial resistance can help to study and conceptualize cancer persisters.