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    Association details:
    Biomarker:NRAS Q61K
    Cancer:Melanoma
    Drug:Zelboraf (vemurafenib) (BRAF inhibitor, BRAF V600E inhibitor)
    Direction:Resistant
    Evidence:
    Evidence Level:
    Resistant: C3 – Early Trials
    New
    Source:
    Clin Cancer Res
    Title:

    Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged after Progression

    Excerpt:
    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.
    DOI:
    10.1158/1078-0432.CCR-13-0661
    Evidence Level:
    Resistant: D – Preclinical
    New
    Source:
    PLoS One
    Title:

    Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

    Excerpt:
    The presence of a secondary mutation in NRASQ61K, in addition to the BRAFV600E mutation, in the in vitro acquired resistant cell line M249-AR4 and in the patient-derived acquired resistant cell line M376, was associated with resistance to vemurafenib but sensitivity to AZD6244,
    DOI:
    10.1371/journal.pone.0028973
    Evidence Level:
    Resistant: D – Preclinical
    New
    Source:
    Nat Commun
    Title:

    Melanoma whole exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance

    Excerpt:
    ...we artificially rendered the V600EB-RAF melanoma cell line, M229, vemurafenib-resistant by either Q61KN-RAS or V600EB-RAF viral transduction (Fig. 3b). Again, high dose vemurafenib treatment was more effective at overcoming drug resistance in V600EB-RAF-transduced M229 than in the same cell line transduced with Q61KN-RAS.
    DOI:
    10.1038/ncomms1727
    Evidence Level:
    Resistant: D – Preclinical
    New
    Source:
    Nature
    Title:

    Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

    Excerpt:
    We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines...Overexpression of PDGFRβ or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines.
    DOI:
    10.1038/nature09626