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Clinical Benefit of Niraparib to TKI/mTORi-Resistance Metastatic ccRCC With BAP1-Frame Shift Mutation: Case Report
Bi-Jun Lian1, Ke Zhang2, Xu-Dong Fang1
1Department of Oncologic and Urologic Surgery, The 903rd People's Liberation Army (PLA) Hospital, Wenzhou Medical University, Hangzhou, China.
Abstract:
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. The top four mutant genes affecting the occurrence and progression of ccRCC are VHL, PBRM1, BAP1, and SETD2, respectively. Tyrosine kinase/mammalian target of rapamycin inhibitors (TKI/mTORis) with or without immunotherapy are the standard and effective therapy to metastatic ccRCC. Once TKI/mTORis fail to ccRCC, there is still a lack of other effective therapies. In this study, we reported a case in which a metastatic ccRCC patient (T2aN1M1) presented resistance after a 28-month treatment by sorafenib-axitinib-everolimus (TKI-TKI-mTORi). Subsequently, a frame shift pathogenic mutation, c.799_800del (p.Q267fs) in the exon10 of BAP1 in ccRCC, was revealed by targeted sequencing. Oral administration of nilapanib (PARP inhibitor) was further given, which may provide a new therapy for TKI/mTORi-resistance metastatic ccRCC. Fortunately, a partial response has been achieved and lasted for 5 months. Since the frequency of BAP1 mutations in ccRCC patients was approximately 10%-20%, as reported previously, we also tried to explore the potential mechanisms benefitting from the nilapanib. Moreover, the literature concerning BAP1 mutation and associated cancers including ccRCC is reviewed.
Insights
Clear cell renal cell carcinoma (ccRCC) patients resistant to standard therapies may benefit from PARP inhibitors. A patient with a BAP1 mutation showed partial response to nilapanib after TKI/mTORi failure, suggesting a new therapeutic avenue.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer subtype.
- VHL, PBRM1, BAP1, and SETD2 are key genes in ccRCC development.
- Tyrosine kinase/mammalian target of rapamycin inhibitors (TKI/mTORis) are standard for metastatic ccRCC, but resistance limits treatment options.
Observation:
- A metastatic ccRCC patient (T2aN1M1) developed resistance after 28 months of TKI-TKI-mTORi therapy (sorafenib-axitinib-everolimus).
- Targeted sequencing identified a frameshift mutation (c.799_800del, p.Q267fs) in exon 10 of the BAP1 gene.
- The patient received oral nilapanib, a poly (ADP-ribose) polymerase (PARP) inhibitor.
Findings:
- The patient achieved a partial response lasting 5 months with nilapanib treatment.
- This suggests nilapanib may be a viable therapy for TKI/mTORi-resistant metastatic ccRCC.
- The study explores potential mechanisms of nilapanib efficacy in BAP1-mutated ccRCC.
Implications:
- BAP1 mutations occur in 10%-20% of ccRCC patients, highlighting the potential relevance of this finding.
- Nilapanib offers a potential new therapeutic strategy for a subset of ccRCC patients who have exhausted standard treatments.
- Further research into BAP1 mutations and PARP inhibitor mechanisms in ccRCC is warranted.
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