Establishment of novel cholangiocarcinoma cell lines with ARID1A deficiency and preclinical validation of synthetic lethality therapies

Abstract

Cholangiocarcinoma (CCA) is a highly lethal malignancy with poor prognosis due to its resistance to conventional chemotherapy and limited number of targetable mutations. The recurrent loss-of-function mutation of the tumor suppressor ARID1A represents a key vulnerability potentially exploitable via synthetic lethality. To advance research in this area, we successfully established and characterized two novel CCA cell lines, SiSP-K01 and SiSP-K05, derived from moderately differentiated intrahepatic CCA. Both models were confirmed to carry ARID1A heterozygous loss and complete protein depletion, authentically reproducing the target genotype. Comprehensive molecular and phenotypic profiling (including karyotype, growth kinetics, 100% in vivo tumorigenesis, and tumor marker expression) confirmed their fidelity to the patient tissue and CCA lineage. Importantly, exome and transcriptome analysis not only validated the cell lines but also revealed an associated derangement of the PI3K/AKT signaling pathway. Based on this molecular finding, we performed drug screening and demonstrated that these ARID1A-deficient CCA cell lines are hypersensitive to inhibition by both PI3K/AKT and PARP inhibitors. The SiSP-K01 and SiSP-K05 cell lines are therefore critical new preclinical models suitable for functional studies of ARID1A deficiency and the development of targeted therapies for CCA.