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

Ileine M. Sanchez, Timothy J. Purwin, Inna Chervoneva, Dan A. Erkes, Mai Q. Nguyen, Michael A. Davies, Katherine L. Nathanson, Kristel Kemper, Daniel S. Peeper, Andrew E. Aplin

Research output: Contribution to journalArticleAcademicpeer-review

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 reactivation 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 (CRT) 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.
Original languageEnglish
Pages (from-to)1637-1648
JournalMolecular Cancer Therapeutics
Volume18
Issue number9
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Cite this

Sanchez, I. M., Purwin, T. J., Chervoneva, I., Erkes, D. A., Nguyen, M. Q., Davies, M. A., ... Aplin, A. E. (2019). In vivo ERK1/2 reporter predictively models response and resistance to combined BRAF and MEK inhibitors in melanoma. Molecular Cancer Therapeutics, 18(9), 1637-1648. https://doi.org/10.1158/1535-7163.MCT-18-1056