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BMC Syst Biol. 2018 Apr 4;12(1):33. doi: 10.1186/s12918-018-0554-1.

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma.

Author information

1
Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, 2500 North Lake Road, Merced, CA, 95343, USA.
2
Department of Medicine, School of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, 92697, USA.
3
The State Key Laboratory of Medical Genetics and School of Life Sciences, Department of Molecular Biology, Central South University, Changsha, 410078, China.
4
Department of Medicine, School of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, 92697, USA. liufe@uci.edu.
5
Department of Epidemiology, School of Medicine, University of California, Irvine, CA, 92697, USA. liufe@uci.edu.
6
Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, 2500 North Lake Road, Merced, CA, 95343, USA. filipp@ucmerced.edu.

Abstract

BACKGROUND:

Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma.

METHODS:

The cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential.

RESULTS:

Downregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors.

CONCLUSIONS:

The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy-resistant cancer.

KEYWORDS:

Adaptation; Cancer systems biology; Drug resistance; Genetic selection; Master regulator; Melanogenesis; Melanoma; Non-genomic; Omics; Precision medicine; RNA-Seq; Regulome; Rewiring; Therapy resistance; Transcription factor; Transcriptomics; Upstream regulator analysis

PMID:
29615030
PMCID:
PMC5883534
DOI:
10.1186/s12918-018-0554-1
[Indexed for MEDLINE]
Free PMC Article

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