Reversion of pathogenic BRCA1 L1780P mutation confers resistance to PARP and ATM inhibitor in breast cancer
Se-Young Jo,
Jeong Dong Lee,
Jeongsoo Won,
Jiho Park,
Taeyong Kweon,
Seongyeon Jo,
Joohyuk Sohn,
Seung-Il Kim,
Sangwoo Kim,
Hyung Seok Park
Affiliations
Se-Young Jo
Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
Jeong Dong Lee
Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
Jeongsoo Won
Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
Jiho Park
Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
Taeyong Kweon
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Medical Science, Yonsei University College of Medicine, Seoul, Korea
Seongyeon Jo
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Medical Science, Yonsei University College of Medicine, Seoul, Korea
Joohyuk Sohn
Division of Medical Oncology, Department of Internal Medicine Yonsei University College of Medicine, Seoul, Korea
Seung-Il Kim
Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
Sangwoo Kim
Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Postech Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang, Korea; Corresponding author
Hyung Seok Park
Department of Surgery, Yonsei University College of Medicine, Seoul, Korea; Corresponding author
Summary: This study investigates the molecular characteristics and therapeutic implications of the BRCA1 L1780P mutation, a rare variant prevalent among Korean hereditary breast cancer patients. Using patient-derived xenograft (PDX) models and cell lines (PDX-derived cell line) from carriers, sequencing analyses revealed loss of heterozygosity (LOH) at the BRCA1 locus, with one patient losing the wild-type allele and the other mutated allele. This reversion mutation may cf. resistance to homologous recombination deficiency (HRD)-targeting drugs such as PARP inhibitors (PARPi) and ATM inhibitors (ATMi). Although HRDetect and CHORD analyses confirmed a strong association between the L1780P mutation and HRD, effective initially, drug resistance developed in cases with reversion mutations. These findings underscore the complexity of using HRD prediction in personalized treatment strategies for breast cancer patients with BRCA1/2 mutations, as resistance may arise in reversion cases despite high HRD scores.
