Transcriptomics

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MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [RNA-Seq]


ABSTRACT: The MAP Kinase pathway is the index oncogenic signaling towards which many compounds have been developed for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). How targeted MEK1/2 inhibition (MEKi) alters the tumor-microenvironment (TME) of PDA is poorly understood. Here, we showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype, while short term MEKi treatment in mouse PDA induced subtype switching. Moreover, MEKi induced depletion of tumor-infiltrating macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early during in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Since tumor-associated macrophages are consistently reported to interfere with gemcitabine uptake by PDA cells, we tested a sequential combination of MEKi and gemcitabine, which showed superior antitumor activity in vivo. These findings suggest that MEKi-induced TME remodeling might be exploited to increase therapeutic responses in PDA.

ORGANISM(S): Mus musculus

PROVIDER: GSE138306 | GEO | 2023/12/31

REPOSITORIES: GEO

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