PMC10034383_01
Representative pre- (upper row) and post-olaparib (lower row) treatment showing radiologic evidence in a 52-year-old man with gallbladder cancer harboring BRCA1 mutation. After 2 months of olaparib treatment, extensive metastatic lesions that involved the primary tumor (white arrow) and liver invasion (white arrowheads) became markedly reduced, while the retroperitoneal lymph nodes (long white arrows) and left supraclavicular lymph nodes (long white dotted arrows) disappeared when compared with those in the pre-olaparib treatment CT and PET/CT images.
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In the intravenous contrast-enhanced CT and positron emission tomography (PET)/CT, the images showed gallbladder cancer with liver invasion ( Figure 1 ). CT and PET/CT exhibited favorable responses of the tumor to the treatment ( Figure 1 ). Similar results were obtained in colony formation and EdU assays of olaparib and/or afatinib on GBC cell lines ectopically expressing BRCA1 p.Arg1325Lys together with ERBB3 p.Gly337Arg mutations ( Supplementary Material Figures 1, 2 ).
Histopathological examination of the specimens in pre- and post-olaparib treatment. (A) The cells (black arrow) from the infiltrating liver in pre-olaparib treatment are markedly pleomorphic with enlarged irregular nuclei (hematoxylin and eosin; magnification x400). (B, C) After treatment with olaparib, only a very limited amount of cancer cells (black arrow) remained, and intense fibrosis developed (magnification x100 in panel B and x400 in panel (C). (D, E) The resected lymph node was negative for malignancy (magnification x100 in panel D and x400 in panel E).
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An endoscopic metal biliary endoprosthesis (EMBE) was engaged first to release the biliary obstruction and the needle biopsy from the liver confirmed adenocarcinoma with gallbladder cancer origin ( Figure 2A ). Thus, an R0 resection was achieved following olaparib treatment ( Figure 2 ). Similar results were obtained in colony formation and EdU assays of olaparib and/or afatinib on GBC cell lines ectopically expressing BRCA1 p.Arg1325Lys together with ERBB3 p.Gly337Arg mutations ( Supplementary Material Figures 1, 2 ).
Cell viability of GBC-SD and NOZ cells expressing BRCA1 p.Arg1325Lys and ERBB3 p.Gly337Arg mutation. (A) GBC-SD cells expressing BRCA1 wild type (wt) or BRCA1 p.Arg1325Lys (mut) or both BRCA1 p.Arg1325Lys (mut) and ERBB3 p.Gly337Arg (mut) responded to olaparib (20 muM) over 192 h. (B) NOZ cells expressing both BRCA1 and ERBB3 wt or BRCA1 p.Arg1325Lys and ERBB3 p.Gly337Arg mutation responded to olaparib (20 muM) and afatinib (10 muM). (C) GBC-SD cells expressing both BRCA1 p.Arg1325Lys and ERBB3 p.Gly337Arg mutation responded to olaparib and afatinib. (D) NOZ cells expressing both BRCA1 p.Arg1325Lys and ERBB3 p.Gly337Arg mutation responded to olaparib and afatinib.
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The results showed that GBC-SD cell lines with only BRCA1 p.Arg1325Lys mutation were more sensitive to olaparib when compared with the cells expressing the wild type ( Figures 3A, B ). However, cells with dual mutations of BRCA1 p.Arg1325Lys and ERBB3 p.Gly337Arg remarkably exhibited olaparib resistance ( Figures 3A, B ). Nevertheless, when afatinib was added, the sensitivity of these mutation cells to both these drugs resumed, and the effect of combined therapy was stronger than that of a single drug ( Figures 3C, D ).