Advertisement
Journal of Investigative Dermatology Home

Oncogenic KIT Induces Replication Stress and Confers Cell Cycle Checkpoint Vulnerability in Melanoma

  • Author Footnotes
    4 These authors contributed equally to this work.
    Ching-Ni Njauw
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Search for articles by this author
  • Author Footnotes
    4 These authors contributed equally to this work.
    Zhenyu Ji
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Search for articles by this author
  • Duc Minh Pham
    Affiliations
    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
    Search for articles by this author
  • Antoine Simoneau
    Affiliations
    Mass General Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
    Search for articles by this author
  • Raj Kumar
    Affiliations
    Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Search for articles by this author
  • Keith T. Flaherty
    Affiliations
    Mass General Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
    Search for articles by this author
  • Lee Zou
    Affiliations
    Mass General Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
    Search for articles by this author
  • Hensin Tsao
    Correspondence
    Correspondence: Hensin Tsao, Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Edwards 221, 50 Blossom Street, Boston, Massachusetts 02114, USA.
    Affiliations
    Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Mass General Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
    Search for articles by this author
  • Author Footnotes
    4 These authors contributed equally to this work.
Published:October 20, 2021DOI:https://doi.org/10.1016/j.jid.2021.07.188
      Acral and mucosal melanomas arise from sun-protected sites, disproportionately impact darker-skinned individuals, and exact higher mortality than common types of cutaneous melanoma. Genetically, acral and mucosal melanomas harbor more alterations of KIT than typical cutaneous melanomas. Because KIT-mutated melanomas remain largely treatment resistant, we set out to create a faithful murine KIT-driven allograft model to define newer therapeutic strategies. Using the prevalent human KITK642E activating mutation, the murine mKITK641E cellular avatars show features of transformation in vitro and tumorigenicity in immunocompetent C57BL/6J mice. mKITK641E cells proliferate more rapidly, exhibit greater chromosomal aberrations, and sustain three-dimensional spheroid expansion and aggressive tumor growth in C57BL/6J mice compared with their vector-controlled cells. We further verified the functional dependence of these cells on KITK641E with both genetic and pharmacologic suppression. Using these cells, we performed a screen of 199 kinase inhibitors and identified a selective vulnerability to Chk1/ATR inhibition in the KITK641E-activated cells. Mechanistically, we subsequently showed that KITK641E induces a significantly increased level of replication stress compared with murine vector‒controlled cells. These results showcase an allograft model of human KIT-driven melanomas, which uncovered an unappreciated role for replication stress in KIT melanomagenesis and implicated a possible therapeutic strategy with Chk1/ATR inhibitors.

      Abbreviations:

      FDR (false discovery rate), mVec (murine vector controlled), PBS-T (PBS + 0.05% Tween 20), RS (replication stress)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      PDF Download and 24 Hours Online Access
      Society Members (SID/ESDR), remember to log in for access.

      Subscribe:

      Subscribe to Journal of Investigative Dermatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Burrell R.A.
        • McClelland S.E.
        • Endesfelder D.
        • Groth P.
        • Weller M.C.
        • Shaikh N.
        • et al.
        Replication stress links structural and numerical cancer chromosomal instability [published correction appears in Nature 2013;500:490].
        Nature. 2013; 494: 492-496
        • Cancer Genome Atlas Network
        Genomic classification of cutaneous melanoma.
        Cell. 2015; 161: 1681-1696
        • Curtin J.A.
        • Busam K.
        • Pinkel D.
        • Bastian B.C.
        Somatic activation of KIT in distinct subtypes of melanoma.
        J Clin Oncol. 2006; 24: 4340-4346
        • Curtin J.A.
        • Fridlyand J.
        • Kageshita T.
        • Patel H.N.
        • Busam K.J.
        • Kutzner H.
        • et al.
        Distinct sets of genetic alterations in melanoma.
        N Engl J Med. 2005; 353: 2135-2147
        • Dai Y.
        • Grant S.
        Targeting Chk1 in the replicative stress response.
        Cell Cycle. 2010; 9: 1025
        • Gong H.Z.
        • Zheng H.Y.
        • Li J.
        The clinical significance of KIT mutations in melanoma: a meta-analysis.
        Melanoma Res. 2018; 28: 259-270
        • Hayward N.K.
        • Wilmott J.S.
        • Waddell N.
        • Johansson P.A.
        • Field M.A.
        • Nones K.
        • et al.
        Whole-genome landscapes of major melanoma subtypes.
        Nature. 2017; 545: 175-180
        • Kotsantis P.
        • Petermann E.
        • Boulton S.J.
        Mechanisms of oncogene-induced replication stress: jigsaw falling into place.
        Cancer Discov. 2018; 8: 537-555
        • Lee J.H.
        • Zhang X.
        • Jung W.Y.
        • Chae Y.S.
        • Park J.J.
        • Kim I.
        DNA ploidy and c-Kit mutation in gastrointestinal stromal tumors.
        World J Gastroenterol. 2004; 10: 3475-3479
        • Meng D.
        • Carvajal R.D.
        KIT as an oncogenic driver in melanoma: an update on clinical development.
        Am J Clin Dermatol. 2019; 20: 315-323
        • Merrick C.J.
        • Jackson D.
        • Diffley J.F.
        Visualization of altered replication dynamics after DNA damage in human cells.
        J Biol Chem. 2004; 279: 20067-20075
        • Pardanani A.
        Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management.
        Am J Hematol. 2019; 94: 363-377
        • Reilley M.J.
        • Bailey A.
        • Subbiah V.
        • Janku F.
        • Naing A.
        • Falchook G.
        • et al.
        Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies.
        J Immunother Cancer. 2017; 5: 35
        • Rubin B.P.
        • Antonescu C.R.
        • Scott-Browne J.P.
        • Comstock M.L.
        • Gu Y.
        • Tanas M.R.
        • et al.
        A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E.
        Cancer Res. 2005; 65: 6631-6639
        • Sanjiv K.
        • Hagenkort A.
        • Calderón-Montaño J.M.
        • Koolmeister T.
        • Reaper P.M.
        • Mortusewicz O.
        • et al.
        Cancer-specific synthetic lethality between ATR and CHK1 kinase activities [published correction appears in Cell Rep 2016;17:3407–3416].
        Cell Rep. 2016; 14: 298-309
        • Sato H.
        • Niimi A.
        • Yasuhara T.
        • Permata T.B.M.
        • Hagiwara Y.
        • Isono M.
        • et al.
        DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells.
        Nat Commun. 2017; 8: 1751
        • Seiler J.A.
        • Conti C.
        • Syed A.
        • Aladjem M.I.
        • Pommier Y.
        The intra-S-phase checkpoint affects both DNA replication initiation and elongation: single-cell and -DNA fiber analyses.
        Mol Cell Biol. 2007; 27: 5806-5818
        • von Mehren M.
        • Joensuu H.
        Gastrointestinal stromal tumors.
        J Clin Oncol. 2018; 36: 136-143
        • Wilhelm T.
        • Olziersky A.M.
        • Harry D.
        • De Sousa F.
        • Vassal H.
        • Eskat A.
        • et al.
        Mild replication stress causes chromosome mis-segregation via premature centriole disengagement.
        Nat Commun. 2019; 10: 3585
        • Zeman M.K.
        • Cimprich K.A.
        Causes and consequences of replication stress.
        Nat Cell Biol. 2014; 16: 2-9