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  1. Article ; Online: Mutations in the IFNγ-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment.

    Nguyen, Tan-Trieu / Ramsay, LeeAnn / Ahanfeshar-Adams, Mozhdeh / Lajoie, Mathieu / Schadendorf, Dirk / Alain, Tommy / Watson, Ian R

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2021  Volume 27, Issue 12, Page(s) 3432–3442

    Abstract: Purpose: Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the IFNγ-JAK-STAT pathway as an immune checkpoint inhibitor (ICI) resistance mechanism in a subset of patients with melanoma. We hypothesized ICI ... ...

    Abstract Purpose: Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the IFNγ-JAK-STAT pathway as an immune checkpoint inhibitor (ICI) resistance mechanism in a subset of patients with melanoma. We hypothesized ICI resistance mutations in the IFNγ pathway would simultaneously render melanomas susceptible to oncolytic virus (OV) therapy.
    Experimental design: Cytotoxicity experiments were performed with a number of OVs on a matched melanoma cell line pair generated from a baseline biopsy and a progressing lesion with complete
    Results: The melanoma line from an anti-PD-1 progressing lesion was 7- and 22-fold more sensitive to the modified OVs, herpes simplex virus 1 (HSV1-dICP0) and vesicular stomatitis virus (VSV-Δ51), respectively, compared with the line from the baseline biopsy. RNAi, JAK1/2 inhibitor studies, and
    Conclusions: We provide mechanistic support for the use of OVs as a precision medicine strategy for both salvage therapy in ICI-resistant and first-line treatment in melanomas with IFNγ-JAK-STAT pathway mutations. Our study also supports JAK inhibitor-OV combination therapy for treatment-naïve melanomas without IFN signaling defects.
    MeSH term(s) Animals ; Cell Line, Tumor ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Janus Kinases/genetics ; Janus Kinases/metabolism ; Melanoma, Experimental/genetics ; Melanoma, Experimental/therapy ; Mice ; Mutation ; Oncolytic Viruses/genetics ; STAT Transcription Factors/genetics ; STAT Transcription Factors/metabolism ; Signal Transduction
    Chemical Substances Immune Checkpoint Inhibitors ; STAT Transcription Factors ; Janus Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2021-02-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-20-3365
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor combination therapy.

    Rajkumar, Shivshankari / Berry, Diana / Heney, Kayla A / Strong, Colton / Ramsay, LeeAnn / Lajoie, Mathieu / Alkallas, Rached / Nguyen, Tan-Trieu / Thomson, Cameron / Ahanfeshar-Adams, Mozhdeh / Dankner, Matthew / Petrella, Teresa / Rose, April A N / Siegel, Peter M / Watson, Ian R

    Cell reports

    2022  Volume 39, Issue 1, Page(s) 110634

    Abstract: Although combination BRAF/MEK inhibition has produced significant survival benefits for BRAF p.V600 mutant melanomas, targeted therapies approved for BRAF non-p.V600 mutant melanomas remain limited. Through the analysis of 772 cutaneous melanoma exomes, ... ...

    Abstract Although combination BRAF/MEK inhibition has produced significant survival benefits for BRAF p.V600 mutant melanomas, targeted therapies approved for BRAF non-p.V600 mutant melanomas remain limited. Through the analysis of 772 cutaneous melanoma exomes, we reveal that BRAF non-p.V600 mutations co-occurs more frequently with NF1 loss, but not with oncogenic NRAS mutations, than expected by chance. We present cell signaling data, which demonstrate that BRAF non-p.V600 mutants can signal as monomers and dimers within an NF1 loss context. Concordantly, BRAF inhibitors that inhibit both monomeric and dimeric BRAF synergize with MEK inhibition to significantly reduce cell viability in vitro and tumor growth in vivo in BRAF non-p.V600 mutant melanomas with co-occurring NF1 loss-of-function mutations. Our data suggest that patients harboring BRAF non-p.V600 mutant melanomas may benefit from current FDA-approved BRAF/MEK inhibitor combination therapy currently reserved for BRAF p.V600 mutant patients.
    MeSH term(s) Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Mitogen-Activated Protein Kinase Kinases/genetics ; Mutation/genetics ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins B-raf/genetics ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics
    Chemical Substances Protein Kinase Inhibitors ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
    Language English
    Publishing date 2022-04-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.110634
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Multi-omic analysis reveals significantly mutated genes and DDX3X as a sex-specific tumor suppressor in cutaneous melanoma.

    Alkallas, Rached / Lajoie, Mathieu / Moldoveanu, Dan / Hoang, Karen Vo / Lefrançois, Philippe / Lingrand, Marine / Ahanfeshar-Adams, Mozhdeh / Watters, Kevin / Spatz, Alan / Zippin, Jonathan H / Najafabadi, Hamed S / Watson, Ian R

    Nature cancer

    2020  Volume 1, Issue 6, Page(s) 635–652

    Abstract: The high background tumor mutation burden in cutaneous melanoma limits the ability to identify significantly mutated genes (SMGs) that drive this cancer. To address this, we performed a mutation significance study of over 1,000 melanoma exomes, combined ... ...

    Abstract The high background tumor mutation burden in cutaneous melanoma limits the ability to identify significantly mutated genes (SMGs) that drive this cancer. To address this, we performed a mutation significance study of over 1,000 melanoma exomes, combined with a multi-omic analysis of 470 cases from The Cancer Genome Atlas. We discovered several SMGs with co-occurring loss-of-heterozygosity and loss-of-function mutations, including PBRM1, PLXNC1 and PRKAR1A, which encodes a protein kinase A holoenzyme subunit. Deconvolution of bulk tumor transcriptomes into cancer, immune and stromal components revealed a melanoma-intrinsic oxidative phosphorylation signature associated with protein kinase A pathway alterations. We also identified SMGs on the X chromosome, including the RNA helicase DDX3X, whose loss-of-function mutations were exclusively observed in males. Finally, we found that tumor mutation burden and immune infiltration contain complementary information on survival of patients with melanoma. In summary, our multi-omic analysis provides insights into melanoma etiology and supports contribution of specific mutations to the sex bias observed in this cancer.
    MeSH term(s) Biomarkers, Tumor/genetics ; Cyclic AMP-Dependent Protein Kinases ; DEAD-box RNA Helicases/genetics ; Female ; Humans ; Male ; Melanoma/genetics ; Skin Neoplasms/genetics ; Melanoma, Cutaneous Malignant
    Chemical Substances Biomarkers, Tumor ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; DDX3X protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2020-06-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2662-1347
    ISSN (online) 2662-1347
    DOI 10.1038/s43018-020-0077-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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