HSP70 inhibition blocks adaptive resistance and synergizes with MEK inhibition for the treatment of NRAS-mutant melanoma.

ABSTRACT: NRAS-mutant melanoma is currently a challenge to treat. This is due to an absence of inhibitors directed against mutant NRAS, along with adaptive and acquired resistance of this tumor type to inhibitors in the MAPK pathway. Inhibitors to MEK (mitogen-activated protein kinase kinase) have shown some promise for NRAS-mutant melanoma. In this work we explored the use of MEK inhibitors for NRAS-mutant melanoma. At the same time we investigated the impact of the brain microenvironment, specifically astrocytes, on the response of a melanoma brain metastatic cell line to MEK inhibition. These parallel avenues led to the surprising finding that astrocytes enhance the sensitivity of melanoma tumors to MEK inhibitors (MEKi). We show that MEKi cause an upregulation of the transcription factor ID3, wh

SUBMITTER: Parris JLD 

PROVIDER: S-EPMC8849551 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature