An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition.
An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition.
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DOI：
10.1084/jem.20160855
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发表时间：
2017-06-05
期刊：
影响因子：
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通讯作者：
Hurlstone A
中科院分区：
文献类型：
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作者：
Young HL;Rowling EJ;Bugatti M;Giurisato E;Luheshi N;Arozarena I;Acosta JC;Kamarashev J;Frederick DT;Cooper ZA;Reuben A;Gil J;Flaherty KT;Wargo JA;Vermi W;Smith MP;Wellbrock C;Hurlstone A
Drug tolerance brought about by reversible adaptive responses precedes the emergence of irreversible mutation-driven drug resistance and sustains tumor cells when at their most vulnerable. Young et al. delineate a signaling relay incorporating IL-1 and CXCR2 ligands emanating from melanoma-associated macrophages and fibroblasts, respectively, that confer tolerance to MAPK inhibitors. Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatment.
