TY - JOUR
T1 - HSP70 inhibition blocks adaptive resistance and synergizes with MEK inhibition for the treatment of NRAS-mutant melanoma
AU - Parris, Joshua L D
AU - Barnoud, Thibaut
AU - Leu, Julia I-Ju
AU - Leung, Jessica C
AU - Ma, Weili
AU - Kirven, Nicole A
AU - Poli, Adi Naryana Reddy
AU - Kossenkov, Andrew V
AU - Liu, Qin
AU - Salvino, Joseph M
AU - George, Donna L
AU - Weeraratna, Ashani T
AU - Chen, Qing
AU - Murphy, Maureen E
N1 - Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research.
PY - 2021/10
Y1 - 2021/10
N2 - 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 have shown some promise for NRAS-mutant melanoma. In this work, we explored the use of MEK inhibitors for NRASmutant 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 transcriptional regulator ID3, which confers resistance. This upregulation of ID3 is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEKi, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEKi against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma. Significance: MEKi are currently used for NRAS-mutant melanoma, but have shown modest efficacy as single agents. This research shows a synergistic effect of combining HSP70 inhibitors with MEKi for the treatment of NRAS mutant melanoma.
AB - 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 have shown some promise for NRAS-mutant melanoma. In this work, we explored the use of MEK inhibitors for NRASmutant 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 transcriptional regulator ID3, which confers resistance. This upregulation of ID3 is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEKi, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEKi against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma. Significance: MEKi are currently used for NRAS-mutant melanoma, but have shown modest efficacy as single agents. This research shows a synergistic effect of combining HSP70 inhibitors with MEKi for the treatment of NRAS mutant melanoma.
KW - Mice
KW - Animals
KW - Mitogen-Activated Protein Kinase Kinases
KW - GTP Phosphohydrolases/genetics
KW - Membrane Proteins/genetics
KW - Mutation
KW - Melanoma/drug therapy
KW - Protein Kinase Inhibitors/pharmacology
KW - Tumor Microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85129121971&partnerID=8YFLogxK
M3 - Article
C2 - 35187538
SN - 2767-9764
VL - 1
SP - 17
EP - 29
JO - Cancer Research Communications
JF - Cancer Research Communications
IS - 1
ER -