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Autor/a
Molina Gutiérrez, Cristina
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Abstract
Mutations in the IDH1 gene are found in about 20% of patients with intrahepatic cholangiocarcinoma (iCCA). Nowadays, the search for efficient therapies for these tumors is a great challenge due to their heterogeneity and display of non-specific and late symptoms with an unfavorable prognosis. Some studies suggest that IDH1-mutated tumors may have a deficiency in the high-fidelity DNA double-strand break (DSB) repair pathway, known as homologous recombination repair (HRR).
Therefore, we hypothesized that the evaluation of the DNA repair capacity in IDH1-mutated tumors could help to elucidate whether the use of agents targeting the HRR pathway, such as PARP inhibitors (PARPi), which could be a novel therapeutic strategy for iCCA.
We evaluated the functionality of the HRR pathway with the RAD51predict test in wild-type (WT) and IDH1-mutated (IDH1-mut) tumor cells obtained using in vivo and in vitro systems. In particular, commercially - available cells lines (HuCCT1 WT and Snu1079 IDH1-mut), patient-derived tumor xenograft (PDX) models (12 WT and 7 IDH1-mut) and patient samples (2 WT and 4 IDH1-mut, being 1 untreated primary samples and 5 samples taken after chemotherapy) were used in this study. RAD51predict is an immunofluorescence - based assay capable of determining the status of the HRR pathway and predicting the response to PARPi. Functional HRR deficiency (HRD) was predefined as RAD51 score ≤ 10% (RAD51-low).
Our data suggests that HRD is not a common feature of IDH1-mutated tumor cells. Indeed, all cell lines, PDX samples and patient samples, regardless of IDH1 status showed RAD51-high scores, indicating a good capacity to repair the DNA. Only one sample from a patient carrying a mutation BRCA2, an essential gene in HRR, was RAD51-low and, therefore, HRD.
The detection of RAD51 foci in IDH1-mutated tumors indicates a correct HRR function in intrahepatic cholangiocarcinoma previously treated with chemotherapy. Our results suggest that PARPi therapy would not benefit advanced and previously treated patients. The study of the HRR function in the early untreated disease setting is ongoing.
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