期刊
CANCER DISCOVERY
卷 7, 期 11, 页码 1248-1265出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0401
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资金
- Burroughs Wellcome Fund
- NIH [1R01CA176111, P01CA168585, K12CA0906525]
- Ressler Family Foundation
- Melanoma Research Alliance
- Ian Copeland Melanoma Fund
- SWOG/Hope Foundation
- Steven C. Gordon Family Foundation
- American Skin Association
- American Association for Cancer Research-Amgen, Inc. Fellowship in Clinical/Translational Cancer Research [16-40-11-HUGO]
- Department of Defense
- Dermatology Foundation
- National Cancer Center Aggressive Cancer Research Postdoctoral Fellowship
- ASCO
- American Cancer Society Research Professorship
Treatment of advanced BRAF(V600)-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell-intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c(+) immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations. SIGNIFICANCE: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylomewide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell-inflamed, stromal adaptations, many of which are tumor cell-driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy. (C) 2017 AACR.
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