Identification of targetable BRAF ΔN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma
| Autor: | Heather Geiger, Scott Powers, Sadia Rahman, Minsig Choi, A. Rao Chimpiri, Vanessa Felice, Vaidehi Jobanputra, Kazimierz O. Wrzeszczynski, Minita Shah, Mayu O. Frank, Dina Manaa, Vanessa V. Michelini, Kanika Arora, Esra Dikoglu, Robert B. Darnell, Depinder Khaira |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Proto-Oncogene Proteins B-raf Lung Neoplasms Adenocarcinoma medicine.disease_cause 03 medical and health sciences 0302 clinical medicine CDKN2A Pancreatic cancer Carcinoma Non-Small-Cell Lung Oximes medicine neoplasm of the pancreas Biomarkers Tumor Humans neoplasms Protein Kinase Inhibitors 030304 developmental biology Tumor marker Aged 0303 health sciences Mutation Whole Genome Sequencing business.industry Remission Induction Imidazoles Dabrafenib General Medicine medicine.disease digestive system diseases 3. Good health Pancreatic Neoplasms Protein kinase domain 030220 oncology & carcinogenesis Cancer research business Rapid Cancer Communication V600E medicine.drug |
| Zdroj: | Cold Spring Harbor Molecular Case Studies |
| ISSN: | 2373-2873 |
| Popis: | The tumor genome of a patient with advanced pancreatic cancer was sequenced to identify potential therapeutic targetable mutations after standard of care failed to produce any significant overall response. Matched tumor-normal whole-genome sequencing revealed somatic mutations in BRAF, TP53, CDKN2A, and a focal deletion of SMAD4. The BRAF variant was an in-frame deletion mutation (ΔN486_P490), which had been previously demonstrated to be a kinase-activating alteration in the BRAF kinase domain. Working with the Novartis patient assistance program allowed us to treat the patient with the BRAF inhibitor, dabrafenib. The patient's overall clinical condition improved dramatically with dabrafenib. Levels of serum tumor marker dropped immediately after treatment, and a subsequent CT scan revealed a significant decrease in the size of both primary and metastatic lesions. The dabrafenib-induced remission lasted for 6 mo. Preclinical studies published concurrently with the patient's treatment showed that the BRAF in-frame mutation (ΔNVTAP) induces oncogenic activation by a mechanism distinct from that induced by V600E, and that this difference dictates the responsiveness to different BRAF inhibitors. This study describes a dramatic instance of how high-level genomic technology and analysis was necessary and sufficient to identify a clinically logical treatment option that was then utilized and shown to be of clinical value for this individual. |
| Databáze: | OpenAIRE |
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