Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged after Progression
| Autor: | Sylvain Pradervand, K. Muehlethaler, Keith Harshman, Johann Weber, Emanuela Romano, Solange Peters, Daniel E. Speiser, Olivier Michielin, Donata Rimoldi, Alexandra Paillusson |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Proto-Oncogene Proteins B-raf Cancer Research Indoles Skin Neoplasms medicine.medical_treatment Antineoplastic Agents Drug resistance Metastasis 03 medical and health sciences 0302 clinical medicine Gene Order medicine Humans Exome Neoplasm Metastasis Codon Vemurafenib Melanoma 030304 developmental biology Sulfonamides 0303 health sciences business.industry Gene Expression Profiling High-Throughput Nucleotide Sequencing Cancer Immunotherapy medicine.disease 3. Good health Alternative Splicing Amino Acid Substitution Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cutaneous melanoma Immunology Disease Progression Cancer research business medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-13-0661 |
| Popis: | Purpose: To investigate the mechanism(s) of resistance to the RAF-inhibitor vemurafenib, we conducted a comprehensive analysis of the genetic alterations occurring in metastatic lesions from a patient with a BRAFV600E-mutant cutaneous melanoma who, after a first response, underwent subsequent rechallenge with this drug. Experimental Design: We obtained blood and tissue samples from a patient diagnosed with a BRAFV600E-mutant cutaneous melanoma that was treated with vemurafenib and achieved a near-complete response. At progression, he received additional lines of chemo/immunotherapy and was successfully rechallenged with vemurafenib. Exome and RNA sequencing were conducted on a pretreatment tumor and two subcutaneous resistant metastases, one that was present at baseline and previously responded to vemurafenib (PV1) and one that occurred de novo after reintroduction of the drug (PV2). A culture established from PV1 was also analyzed. Results: We identified two NRAS-activating somatic mutations, Q61R and Q61K, affecting two main subpopulations in the metastasis PV1 and a BRAF alternative splicing, involving exons 4–10, in the metastasis PV2. These alterations, known to confer resistance to RAF inhibitors, were tumor-specific, mutually exclusive, and were not detected in pretreatment tumor samples. In addition, the oncogenic PIK3CAH1047R mutation was detected in a subpopulation of PV1, but this mutation did not seem to play a major role in vemurafenib resistance in this metastasis. Conclusions: This work describes the coexistence within the same patient of different molecular mechanisms of resistance to vemurafenib affecting different metastatic sites. These findings have direct implications for the clinical management of BRAF-mutant melanoma. Clin Cancer Res; 19(20); 5749–57. ©2013 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|