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Mol Cancer Ther. 2019 Jul 3. pii: molcanther.1056.2018. doi: 10.1158/1535-7163.MCT-18-1056. [Epub ahead of print]

In vivo ERK1/2 reporter predictively models response and resistance to combined BRAF and MEK inhibitors in melanoma.

Author information

1
Cancer Biology, Thomas Jefferson University.
2
Department of Cancer Biology, Thomas Jefferson University.
3
Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University.
4
Immunology, Thomas Jefferson University.
5
Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.
6
University of Pennsylvania.
7
Molecular Oncology, Netherlands Cancer Institute.
8
Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute.
9
Cancer Biology, Thomas Jefferson University aeaplin004@icloud.com.

Abstract

Combined BRAF and MEK inhibition is a standard of care in patients with advanced BRAF mutant melanoma but acquired resistance remains a challenge that limits response durability. Here we quantitated in vivo ERK1/2 activity and tumor response associated with resistance to combined BRAF and MEK inhibition in mutant BRAF xenografts. We found that ERK1/2 pathway re-activation preceded the growth of resistant tumors. Moreover, we detected a subset of cells that not only persisted throughout long term treatment but restored ERK1/2 signaling and grew upon drug removal. Cell lines derived from combination-resistant tumors (CRTs) exhibited elevated ERK1/2 phosphorylation, which were sensitive to ERK1/2 inhibition. In some CRTs, we detected a tandem duplication of the BRAF kinase domain. Monitoring ERK1/2 activity in vivo was efficacious in predicting tumor response during intermittent treatment. We observed maintained expression of the mitotic regulator, polo-like kinase 1 (Plk1), in melanoma resistant to BRAF and MEK inhibitors. Plk1 inhibition induced apoptosis in CRTs, leading to slowed growth of BRAF and MEK inhibitor-resistant tumors in vivo. These data demonstrate the utility of in vivo ERK1/2 pathway reporting as a tool to optimize clinical dosing schemes and establish suppression of Plk1 as potential salvage therapy for BRAF inhibitor and MEK inhibitor-resistant melanoma.

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