Characterization of Drug-Tolerant Persister Cells in Gastric Cancer

Gastric cancer (GC) is a deadly malignancy; due to its biological and genetic heterogeneity it is indeed challenging to improve GC patient survival through conventional therapeutic approaches. Recently, drug-tolerant persister cells (DTPs) have been identified as a major obstacle in cancer treatment efficacy since they can survive to standard therapies by entering a dormant or quiescent state that allows them to survive under therapy pressure, resulting in drug resistance and eventually relapse. In this study, we have generated and characterized GC DTPs, obtained by treating GC primary cells with the FOLFIRI chemotherapy regimen. After inducing the DTP status these cells show a transient senescence-like phenotype (positive for the senescence marker B-galactosidase). After drug withdrawal these cells reacquire the original transcriptional profile and lose the b-gal positivity. The slow proliferation nature of DTPs was confirmed by down regulation of the proliferation marker KI67 and the upregulation of cell cycle arrest biomarkers such as p21, p53 and pospho-p53, testifying DTP cells ability to arrest proliferation, thus escaping chemotherapy-induced cell death. Even if the vast majority of the FOLFIRI GC DTPs showed PS6 downregulation, the presence of few cycling DTPs in the persister population was observed. Interestingly, we observed that GC DTPs downmodulate the expression of key genes involved in the DNA Mismatch repair and homologous recombination systems, acquiring a status of “temporary BRCAness”. In sum, we have isolated GC DTPs and highlighted a potential vulnerability that will be exploited for a future synthetic lethality approach.