IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma

The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells...

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Autores principales:	Hima Patel, Rosalin Mishra, Nour Yacoub, Samar Alanazi, Mary Kate Kilroy, Joan T. Garrett
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	melanoma BRAF resistance IGF1R IR Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/120f7fae924344028d8f89296f08696d
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spelling	oai:doaj.org-article:120f7fae924344028d8f89296f08696d2021-11-25T17:04:51ZIGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma10.3390/cancers132258632072-6694https://doaj.org/article/120f7fae924344028d8f89296f08696d2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5863https://doaj.org/toc/2072-6694The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.Hima PatelRosalin MishraNour YacoubSamar AlanaziMary Kate KilroyJoan T. GarrettMDPI AGarticlemelanomaBRAFresistanceIGF1RIRNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5863, p 5863 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	melanoma BRAF resistance IGF1R IR Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	melanoma BRAF resistance IGF1R IR Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Hima Patel Rosalin Mishra Nour Yacoub Samar Alanazi Mary Kate Kilroy Joan T. Garrett IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma
description	The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.
format	article
author	Hima Patel Rosalin Mishra Nour Yacoub Samar Alanazi Mary Kate Kilroy Joan T. Garrett
author_facet	Hima Patel Rosalin Mishra Nour Yacoub Samar Alanazi Mary Kate Kilroy Joan T. Garrett
author_sort	Hima Patel
title	IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma
title_short	IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma
title_full	IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma
title_fullStr	IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma
title_full_unstemmed	IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma
title_sort	igf1r/ir mediates resistance to braf and mek inhibitors in braf-mutant melanoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/120f7fae924344028d8f89296f08696d
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IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma

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