An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

Helen Young, Emily Rowling, Mattia Bugatti, Emanuele Giurisato, Nadia Luheshi, Imanol Arozarena, Juan-Carlos Acosta, Jivko Kamarashev, Dennie T Frederick, Zachary A Cooper, Alexandre Reuben, Jesus Gil, Keith T Flaherty, Jennifer A Wargo, William Vermi, Michael Smith, Claudia Wellbrock, Adam Hurlstone

Research output: Contribution to journalArticlepeer-review

162 Downloads (Pure)


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.
Original languageEnglish
JournalJournal of Experimental Medicine
Issue number5
Early online date27 Apr 2017
Publication statusPublished - 1 May 2017

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


Dive into the research topics of 'An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition'. Together they form a unique fingerprint.

Cite this